Polyheterocyclic compounds as mettl3 inhibitors

ABSTRACT

The present invention relates to compounds of formula (I) that function as inhibitors of METTL3 (N6-adenosine-methyltransferase 70 kDa subunit) enzyme activity:X—Y—Z  (I)wherein X, Y and Z are each as defined herein. The present invention also relates to processes for the preparation of these compounds, to pharmaceutical compositions comprising them, and to their use in the treatment of proliferative disorders, such as cancer, and autoimmune diseases, as well as other diseases or conditions in which METTL3 activity is implicated.

FIELD OF THE INVENTION

The present invention relates to certain compounds that function asinhibitors of METTL3 (N6-adenosine-methyltransferase 70 kDa subunit)activity. The present invention also relates to processes for thepreparation of these compounds, to pharmaceutical compositionscomprising them, and to their use in the treatment of proliferativedisorders, such as cancer, autoimmune, neurological, infectious andinflammatory diseases, as well as other diseases or conditions in whichMETTL3 activity is implicated.

BACKGROUND OF THE INVENTION

N6-methyladenosine (m6A) is the most common and abundant covalentmodification of messenger RNA, modulated by ‘writers’, ‘erasers’ and‘readers’ of this mark (Meyer & Jaffrey 2014, Niu Y et al, 2013, Yue etal 2015). Approximately 0.1 to 0.5% of all mRNA adenosines are m6Amodified (Li Y et al 2015). In vitro data have shown that m6A influencesfundamental aspects of mRNA biology, mainly mRNA expression, splicing,stability, localisation and translation (Meyer et al, 2015; Sledz &Jinek 2016). M6A modifications are tissue specific and there issignificant variability in their occurrence profiles in non-diseasedtissues (eg brain, heart, kidney) and diseased tissues and cells (lung,renal, breast, and leukemic cancer cells) (Meyer et al 2012).

The m6A modifications and its erasers and writers such as FTO, ALKBH5,methyltransferase like 3 (METTL3) and METTL14 are associated with majordiseases such as solid organ cancers, leukaemia, type 2 diabetes,neuropsychiatric behavioural and depressive disorders (Chandola et al2015; Koranda et al 2018).

The RNA methyltransferase, METTL3, is the major, but not the soleenzyme, that catalyses m6A modification of RNA. It exists as ahetero-trimeric complex with METTL14 (Liu et al 2014, Wang et al 2016)and Wilm's Tumour Associated Protein (WTAP) (Ping et al 2014). Catalyticactivity resides in METTL3, which transfers a methyl group from theco-factor S-adenosyl methionine to the substrate RNA and METTL14facilitates substrate RNA binding. WTAP localises the complex inspecific nuclear regions and also localises RNA substrates to thecomplex (Wang X et al 2016).

METTL3 has been reported to play a role in many aspects of thedevelopment of cancer (Fry et al 2018). Genetic knockdown of METTL3 inlung cancer cell lines (A549, H1299 and H1792) and HeLa cells leads todecreased growth, survival and invasion of human lung cancer cells (LinS et al 2016). METTL3 is significantly up-regulated in human bladdercancer (Cheng et al 2019). Knockdown of METTL3 drastically reducedbladder cancer cell proliferation, invasion, and survival in vitro andtumorigenicity in vivo. AF4/FMR2 family member 4 (AFF4), two keyregulators of NF-κB pathway (IKBKB and RELA) and MYC were furtheridentified as direct targets of METTL3-mediated m6A modification. Inrenal carcinoma cell lines (CAK-1, CAK-2 and ACHN), genetic knockdownreduced cell proliferation via the phosphatidinylinositol 3-kinase(PI3K)/AKT/mammalian target of rapamycin (mTOR) signalling pathway (Li Xet al 2017).

Recently Barbieri et al (2017), defined a set of RNA-modifying enzymesthat are necessary for AML leukaemia and identified a key leukemicpathway for the METTL3 RNA methyltransferase. In this pathway, METTL3 isstably recruited by the CCAAT-box binding transcription factor CEBPZ topromoters of a specific set of active genes, resulting in m6Amethylation of the respective mRNAs and increased translation. Oneimportant target is SP1, an oncogene in several cancers, which regulatesc-MYC expression. Consistent with these findings, it has been reportedthat METTL3 can methylate its targets co-transcriptionally.

The pathway described by Barbieri et al., is critical for AML leukaemia,as three of its components are required for AML cell growth: (i) the m6ARNA methyltransferase METTL3; (ii) the transcription factor CEBPZ, whichtargets this enzyme to promoters; and (iii) SP1, whose translation isdependent upon the m6A modification by METTL3. Together, theobservations of Barbieri et al define METTL3 enzymatic activity as a newcandidate target for the treatment of AML.

In separate, independent studies it has been reported that METTL3 playsan essential role in controlling myeloid differentiation of mammaliannormal hematopoietic and leukemic cells (Vu et al 2017). Forcedexpression of wild type METTL3, but not a mutant METTL3 (with defect incatalytic activity), significantly promotes cell proliferation andinhibits cell differentiation of human cord blood-derived CD34+haematopoietic stem/progenitor cells (HSPCs). Genetic knockdown ofMETTL3 has the opposite effects. METTL3 is highly expressed in AMLcompared to normal HSPCs or other types of cancers. Knockdown of METTL3in human AML cell lines significantly induces cell differentiation andapoptosis and inhibits leukemia progression in mice xeno-transplantedwith MOLM-13 AML cells. The biological function of METTL3 is likelyattributed to the promotion of translation of its mRNA targets such asMYC, BCL-2, and PTEN in an m6A-dependent manner.

Recently, METTL3 mediated m6A modification has been demonstrated to playan important role in T cell homeostasis and signal dependent inductionof mRNA degradation in CD4 positive T cell lineages (Li et al 2017).Deletion of METTL3 in mouse T cells disrupts T cell homeostasis anddifferentiation. In a lymphopenic mouse adoptive transfer model, naiveMett/3-deficient T cells failed to undergo homeostatic expansion andremained in the naive state for up to 12 weeks, thereby preventingcolitis. Consistent with these observations, the mRNAs of SOCS familygenes encoding the STAT signalling inhibitory proteins SOCS1, SOCS3 andCISH were marked by m6A, exhibited slower mRNA decay and showedincreased mRNAs and levels of protein expression in Mettl3-deficientnaive T cells. This increased SOCS family activity consequentlyinhibited IL-7-mediated STAT5 activation and T cell homeostaticproliferation and differentiation. Thus METTL3 mediated m6A methylationhas important roles for inducible degradation of Socs mRNAs in responseto IL-7 signalling in order to reprogram naive T cells for proliferationand differentiation, pointing to a role in auto-immunity.

Recent studies have revealed that depletion of METTL3 leads toalterations in the propagation of diverse viruses (Winkler et al).Following viral infection or stimulation of cells with an inactivatedvirus, deletion of the m6A ‘writer’ METTL3 led to an increase in theinduction of interferon-stimulated genes. Consequently, propagation ofdifferent viruses was suppressed in an interferon-signaling-dependentmanner. Significantly, the mRNA of IFNB, was m6A modified and wasstabilized following repression of METTL3. m6A serves as a negativeregulator of interferon response by dictating the fast turnover ofinterferon mRNAs and consequently facilitating viral propagation.

METTL3-dependent m6A on HBV and HCV viral genome regulates recognitionof the viral genome by RIG-1 RNA sensor. Depletion of METTL3 enhancesviral dsRNA recognition and induces an anti-viral immune response (Kimet al.).

Therefore METTL3 inhibitors may provide a novel therapeutic approach totreat a range of infectious and inflammatory diseases. In particular,they provide a potential treatments for viral diseases (e.g. DNA and RNAviruses).

Furthermore, METTL3-dependent m6A on endogenous mRNAs regulatesrecognition of by MAVS-dependent RNA sensors. Depletion of METTL3enhances endogenous dsRNA recognition and induces an auto-immuneresponse (Gao et al.). This implies that an anti-tumour immune responsemight be enhanced by METTL3 inhibition.

Thus, METTL3 inhibitors may also provide a novel therapeutic approach toenhance an anti-tumour immune response.

REFERENCES

-   Barbieri I, Tzelepis K, Pandolfini L, Shi J, Millen-Zambrano G,    Robson S C, Aspris D, Migliori V, Bannister A J, Han N, De    Braekeleer E, Ponstingl H, Hendrick A, Vakoc C R, Vassiliou G S,    Kouzarides T. Nature. 2017 Dec. 7;552(7683):126-131.-   Chandola U, Das R, Panda B. Brief Funct Genomics. 2015 May;    14(3):169-79.-   Cheng M, Gao Q, Wu M, Liang Y, Zhu F, Zhang Y, Zhang X, Li Y, Sheng    L, Zhang H, Xiong Q, Yuan Q, Oncogene (2019; e-publication ahead of    print).-   Fry N J, Law B A, Ilkayeva O R, Carraway K R, Holley C L, Mansfield    K D. Oncotarget. 2018 Jul. 27;9(58):31231-31243.-   Koranda J L, Dore L, Shi H, Patel M J, Vaasjo L O, Rao M N, Chen K,    Lu Z, Yi Y, Chi W, He C, Zhuang X. Neuron. 2018 Jul. 25; 99(2):    283-292.-   Li H B, Tong J, Zhu S, Batista P J, Duffy E E, Zhao J, Bailis W, Cao    G, Kroehling L, Chen Y, Wang G, Broughton J P, Chen Y G, Kluger Y,    Simon M D, Chang H Y, Yin Z, Flavell R A. Nature. 2017 Aug. 17;548    (7667):338-342-   Li X, Tang J, Huang W, Wang F, Li P, Qin C, Qin Z, Zou Q, Wei J, Hua    L, Yang H, Wang Z. Oncotarget. 2017 Oct. 10;8(56):96103-96116.-   Li Y, Wang Y, Zhang Z, Zamudio A V, Zhao J C. RNA. 2015 August;    21(8):1511-8.-   Lin S, Choe J, Du P, Triboulet R, Gregory R I. Mol Cell. 2016 May    5;62(3):335-345.-   Liu J, Yue Y, Han D, Wang X, Fu Y, Zhang L, Jia G, Yu M, Lu Z, Deng    X, Dai Q, Chen W, He C. Nat Chem Biol. 2014 February;10(2):93-5.-   Meyer K D, Patil D P, Zhou J, Zinoviev A, Skabkin M A, Elemento O,    Pestova T A, Qian S B, Jaffrey S R. Cell. 2015 Nov. 5; 163(4):    999-1010.-   Meyer K D, Jaffrey S R. Nat Rev Mol Cell Biol. 2014 May;    15(5):313-26.-   Meyer K D, Saletore Y, Zumbo P, Elemento O, Mason C E, Jaffrey S R.    Cell. 2012 Jun. 22;149(7):1635-46.-   Niu Y, Zhao X, Wu Y S, Li M M, Wang X J, Yang Y G. Genomics    Proteomics Bioinformatics. 2013 February;11(1):8-17.-   Ping X L, Sun B F, Wang L, Xiao W, Yang X, Wang W J, Adhikari S, Shi    Y, Lv Y, Chen Y S, Zhao X, Li A, Yang Y, Dahal U, Lou X M, Liu X,    Huang J, Yuan W P, Zhu X F, Cheng T, Zhao Y L, Wang X, Rendtlew    Danielsen J M, Liu F, Yang Y G. Cell Res. 2014    February;24(2):177-89.-   Śledź P, Jinek M. Elife. 2016 Sep. 14;5.-   Vu L P, Pickering B F, Cheng Y, Zaccara S, Nguyen D, Minuesa G, Chou    T, Chow A, Saletore Y, MacKay M, Schulman J, Famulare C, Patel M,    Klimek V M, Garrett-Bakelman F E, Melnick A, Carroll M, Mason C E,    Jaffrey S R, Kharas M G. Nat Med. 2017 November;23(11):1369-1376.-   Wang X, Feng J, Xue Y, Guan Z, Zhang D, Liu Z, Gong Z, Wang Q, Huang    J, Tang C, Zou T, Yin P. Nature. 2016 Jun. 23;534(7608):575-8-   Wang P, Doxtader K A, Nam Y. Mol Cell. 2016 Jul. 21;63(2):306-317.-   Winkler R, Gillis E, Lasman L, Safra M, Geula S, Soyris C, Nachshon    A, Tai-Schmiedel J, Friedman N, Le-Trilling Vu T K, Trilling M,    Mandelboim M, Hanna, J H, Schwartz S, Stern-Ginossar N. Nature    Immunology (2018, e-publication ahead of print).-   Yue Y, Liu J, He C. Genes Dev. 2015 Jul. 1;29(13):1343-55.-   Geon-Woo Kim, Hasan Imam, Mohsin Khan, Aleem Siddiqui, J Biol Chem,    (27 Jul. 2020; online publication ahead of print).-   Yimeng Gao, Radovan Vasic, Yuanbin Song, Rhea Teng, Chengyang Liu,    Rana Gbyli, Giulia Biancon, Raman Nelakanti, Kirsten Lobben, Eriko    Kudo, Wei Liu, Anastasia Ardasheva, Xiaoying Fu, Xiaman Wang,    Poorval Joshi, Veronica Lee, Burak Dura, Gabriella Viero, Akiko    Iwasaki, Rong Fan, Andrew Xiao, Richard A Flavell, Hua-Bing Li, Toma    Tebaldi, Stephanie Halene; Immunity (16 Jun. 2020; Volume 52; 6;    p887-1132).-   Rosa M Rubio, Daniel P Depledge, Christopher Bianco, Letitia    Thompson, Ian Mohr; Genes Dev. 2018 Dec. 1;32(23-24):1472-1484.

An object of this invention is to provide inhibitors of METTL3 activity.

SUMMARY OF THE INVENTION

In one aspect, the present invention provides a compound as definedherein, or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention provides a pharmaceuticalcomposition as defined herein which comprises a compound as definedherein, or a pharmaceutically acceptable salt thereof, and one or morepharmaceutically acceptable excipients.

In another aspect, the present invention provides a compound as definedherein, or a pharmaceutically acceptable salt thereof, or apharmaceutical composition as defined herein, for use in therapy.

In another aspect, the present invention provides a compound as definedherein, or a pharmaceutically acceptable salt thereof, or apharmaceutical composition as defined herein, for use in the treatmentof a proliferative condition.

In another aspect, the present invention provides a compound as definedherein, or a pharmaceutically acceptable salt thereof, or apharmaceutical composition as defined herein, for use in the treatmentof cancer. In a particular embodiment, the cancer is a human cancer.

In another aspect, the present invention provides a compound as definedherein, or a pharmaceutically acceptable salt thereof, or apharmaceutical composition as defined herein, for use in the inhibitionof METTL3 activity.

In another aspect, the present invention provides a compound as definedherein, or a pharmaceutically acceptable salt thereof, or apharmaceutical composition as defined herein, for use in promoting animmune response (e.g. anti-viral or anti-tumour immune response).

In another aspect, the present invention provides a compound as definedherein, or a pharmaceutically acceptable salt thereof, or apharmaceutical composition as defined herein, for use in increasing aninnate immune response in a subject.

In another aspect, the present invention provides a compound as definedherein, or a pharmaceutically acceptable salt thereof, or apharmaceutical composition as defined herein, for use in increasing orenhancing an anti-tumour immune response during immune-oncology therapy.

In another aspect, the present invention provides a compound as definedherein, or a pharmaceutically acceptable salt thereof, or apharmaceutical composition as defined herein, for use in the treatmentof an autoimmune disease.

In another aspect, the present invention provides a compound as definedherein, or a pharmaceutically acceptable salt thereof, or apharmaceutical composition as defined herein, for use in the treatmentof a neurological disease.

In another aspect, the present invention provides a compound as definedherein, or a pharmaceutically acceptable salt thereof, or apharmaceutical composition as defined herein, for use in the treatmentof an infectious disease.

In another aspect, the present invention provides a compound as definedherein, or a pharmaceutically acceptable salt thereof, or apharmaceutical composition as defined herein, for use in the treatmentof a viral infection. Suitably, the viral infection is a RNA viralinfection. Suitably, the viral infection is human papillomavirus (HPV)or hepatitis.

In another aspect, the present invention provides a compound as definedherein, or a pharmaceutically acceptable salt thereof, or apharmaceutical composition as defined herein, for use in the treatmentof an inflammatory disease.

In another aspect, the present invention provides the use of a compoundas defined herein, or a pharmaceutically acceptable salt thereof, in themanufacture of a medicament for use in the treatment of a proliferativecondition.

In another aspect, the present invention provides the use of a compoundas defined herein, or a pharmaceutically acceptable salt thereof, in themanufacture of a medicament for use in the treatment of cancer. In aparticular embodiment, the medicament is for use in the treatment ofhuman cancers.

In another aspect, the present invention provides the use of a compoundas defined herein, or a pharmaceutically acceptable salt thereof, in themanufacture of a medicament for the inhibition of METTL3 activity.

In another aspect, the present invention provides the use of a compoundas defined herein, or a pharmaceutically acceptable salt thereof, in themanufacture of a medicament for promoting an immune response (e.g.anti-viral or anti-tumour immune response).

In another aspect, the present invention provides the use of a compoundas defined herein, or a pharmaceutically acceptable salt thereof, in themanufacture of a medicament for for use in increasing an innate immuneresponse in a subject.

In another aspect, the present invention provides the use of a compoundas defined herein, or a pharmaceutically acceptable salt thereof, in themanufacture of a medicament for use in increasing or enhancing ananti-tumour immune response during immune-oncology therapy.

In another aspect, the present invention provides the use of a compoundas defined herein, or a pharmaceutically acceptable salt thereof, in themanufacture of a medicament for use in the treatment of an autoimmunedisease.

In another aspect, the present invention provides the use of a compoundas defined herein, or a pharmaceutically acceptable salt thereof, in themanufacture of a medicament for use in the treatment of a neurologicaldisease.

In another aspect, the present invention provides the use of a compoundas defined herein, or a pharmaceutically acceptable salt thereof, in themanufacture of a medicament for use in the treatment of an infectiousdisease.

In another aspect, the present invention provides the use of a compoundas defined herein, or a pharmaceutically acceptable salt thereof, in themanufacture of a medicament for use in the treatment of a viralinfection. Suitably, the viral infection is a RNA viral infection.Suitably, the viral infection is human papillomavirus (HPV) orhepatitis.

In another aspect, the present invention provides the use of a compoundas defined herein, or a pharmaceutically acceptable salt thereof, in themanufacture of a medicament for use in the treatment of an inflammatorydisease.

In another aspect, the present invention provides a method of inhibitingMETTL3 activity in vitro or in vivo, said method comprising contacting acell with an effective amount of a compound as defined herein, or apharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition as defined herein.

In another aspect, the present invention provides a method of inhibitingcell proliferation in vitro or in vivo, said method comprisingcontacting a cell with an effective amount of a compound as definedherein, or a pharmaceutically acceptable salt, or a pharmaceuticalcomposition as defined herein.

In another aspect, the present invention provides a method of inhibitingmetastasis in vitro or in vivo, said method comprising contacting a cellwith an effective amount of a compound as defined herein, or apharmaceutically acceptable salt, or a pharmaceutical composition asdefined herein.

In another aspect, the present invention provides a method of promotingan immune response (e.g. anti-viral or anti-tumour immune response) in asubject in need thereof, said method comprising administering to thesubject a therapeutically effective amount of a compound as definedherein, or a pharmaceutically acceptable salt, or a pharmaceuticalcomposition as defined herein.

In another aspect, the present invention provides a method of increasingan innate immune response in a subject in need thereof, said methodcomprising administering to the subject a therapeutically effectiveamount of a compound as defined herein, or a pharmaceutically acceptablesalt, or a pharmaceutical composition as defined herein.

In another aspect, the present invention provides a method of increasingor enhancing an anti-tumour immune response during immune-oncologytherapy, said method comprising administering to a subject in needthereof a therapeutically effective amount of a compound as definedherein, or a pharmaceutically acceptable salt, or a pharmaceuticalcomposition as defined herein.

In another aspect, the present invention provides a method of treating aproliferative disorder, said method comprising administering to asubject in need thereof a therapeutically effective amount of a compoundas defined herein, or a pharmaceutically acceptable salt, or apharmaceutical composition as defined herein.

In another aspect, the present invention provides a method of treatingcancer, said method comprising administering to a subject in needthereof a therapeutically effective amount of a compound as definedherein, or a pharmaceutically acceptable salt, or a pharmaceuticalcomposition as defined herein.

In another aspect, the present invention provides a method of treatingan autoimmune disease, said method comprising administering to a subjectin need thereof a therapeutically effective amount of a compound asdefined herein, or a pharmaceutically acceptable salt, or apharmaceutical composition as defined herein.

In another aspect, the present invention provides a method of treating aneurological disease, said method comprising administering to a subjectin need thereof a therapeutically effective amount of a compound asdefined herein, or a pharmaceutically acceptable salt, or apharmaceutical composition as defined herein.

In another aspect, the present invention provides a method of treatingan infectious disease, said method comprising administering to a subjectin need thereof a therapeutically effective amount of a compound asdefined herein, or a pharmaceutically acceptable salt, or apharmaceutical composition as defined herein.

In another aspect, the present invention provides a method of treating aviral infection, said method comprising administering to a subject inneed thereof a therapeutically effective amount of a compound as definedherein, or a pharmaceutically acceptable salt, or a pharmaceuticalcomposition as defined herein. Suitably, the viral infection is a RNAviral infection. Suitably, the viral infection is human papillomavirus(HPV) or hepatitis.

In another aspect, the present invention provides a method of treatingan inflammatory disease, said method comprising administering to asubject in need thereof a therapeutically effective amount of a compoundas defined herein, or a pharmaceutically acceptable salt, or apharmaceutical composition as defined herein.

In one aspect, the present invention provides a combination comprising acompound as defined herein, or a pharmaceutically acceptable saltthereof, with one or more additional therapeutic agents.

The present invention further provides a method of synthesising acompound, or a pharmaceutically acceptable salt, as defined herein.

In another aspect, the present invention provides a compound as definedherein, or a pharmaceutically acceptable salt, obtainable by, orobtained by, or directly obtained by a method of synthesis as definedherein.

In another aspect, the present invention provides novel intermediates asdefined herein which are suitable for use in any one of the syntheticmethods as set out herein.

Preferred, suitable, and optional features of any one particular aspectof the present invention are also preferred, suitable, and optionalfeatures of any other aspect.

DETAILED DESCRIPTION OF THE INVENTION Definitions

Unless otherwise stated, the following terms used in the specificationand claims have the following meanings set out below.

It is to be appreciated that references to “treating” or “treatment”include prophylaxis as well as the alleviation of established symptomsof a condition. “Treating” or “treatment” of a state, disorder orcondition therefore includes: (1) preventing or delaying the appearanceof clinical symptoms of the state, disorder or condition developing in ahuman that may be afflicted with or predisposed to the state, disorderor condition but does not yet experience or display clinical orsubclinical symptoms of the state, disorder or condition, (2) inhibitingthe state, disorder or condition, i.e., arresting, reducing or delayingthe development of the disease or a relapse thereof (in case ofmaintenance treatment) or at least one clinical or subclinical symptomthereof, or (3) relieving or attenuating the disease, i.e., causingregression of the state, disorder or condition or at least one of itsclinical or subclinical symptoms.

A “therapeutically effective amount” means the amount of a compoundthat, when administered to a mammal for treating a disease, issufficient to effect such treatment for the disease. The“therapeutically effective amount” will vary depending on the compound,the disease and its severity and the age, weight, etc., of the mammal tobe treated.

In this specification the term “alkyl” includes both straight andbranched chain alkyl groups. References to individual alkyl groups suchas “propyl” are specific for the straight chain version only andreferences to individual branched chain alkyl groups such as “isopropyl”are specific for the branched chain version only. For example,“C₁₋₆alkyl” includes C₁₋₄alkyl, C₁₋₃alkyl, propyl, isopropyl andt-butyl. A similar convention applies to other radicals, for example“phenyl(C₁₋₆alkyl)” includes phenyl(C₁₋₄alkyl), benzyl, 1-phenylethyland 2-phenylethyl.

The term “(m-nC)” or “Cm-n”, or “(m-nC) group” or “Cm-n” used alone oras a prefix, refers to any group having m to n carbon atoms.

The term “alkenyl”, as used herein, refers to an aliphatic groupcontaining at least one double bond and is intended to include both“unsubstituted alkenyls” and “substituted alkenyls”, the latter of whichrefers to alkenyl moieties having substituents replacing a hydrogen onone or more carbons of the alkenyl group. Such substituents may occur onone or more carbons that are included or not included in one or moredouble bonds. Moreover, such substituents include all those contemplatedfor alkyl groups, as discussed below, except where stability isprohibitive. For example, substitution of alkenyl groups by one or morealkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups iscontemplated.

The term “alkynyl”, as used herein, refers to an aliphatic groupcontaining at least one triple bond and is intended to include both“unsubstituted alkynyls” and “substituted alkynyls”, the latter of whichrefers to alkynyl moieties having substituents replacing a hydrogen onone or more carbons of the alkynyl group. Such substituents may occur onone or more carbons that are included or not included in one or moretriple bonds. Moreover, such substituents include all those contemplatedfor alkyl groups, as discussed above, except where stability isprohibitive. For example, substitution of alkynyl groups by one or morealkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups iscontemplated.

An “alkylene” group is an alkyl group that is positioned between andserves to connect two other chemical groups. Thus, “C₁₋₃alkylene” meansa linear saturated divalent hydrocarbon radical of one to three carbonatoms or a branched saturated divalent hydrocarbon radical of threeatoms, for example, methylene, ethylene, propylene, and the like.

The term “C_(m-n)cycloalkyl” means a hydrocarbon ring containing from mto n carbon atoms, for example “C₃₋₆cycloalkyl” means a hydrocarbon ringcontaining from 3 to 6 carbon atoms, for example, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl. The term “C_(m-n)cycloalkyl” alsoencompasses non-aromatic saturated or partially saturated monocyclic,fused, bridged, or spiro bicyclic carbocyclic ring system(s). The term“C_(m-n)cycloalkyl” includes both monovalent species and divalentspecies. Monocyclic “C_(m-n)cycloalkyl” rings contain from about 3 to 12(suitably from 3 to 8, most suitably from 5 to 6) ring carbon atoms.Bicyclic “C_(m-n)cycloalkyl” contain from 7 to 17 ring carbon atoms,suitably 7 to 12 ring carbon atoms. Bicyclic “C_(m-n)cycloalkyl” ringsmay be fused, spiro, or bridged ring systems.

The term “cycloalkoxy” means a cycloalkyl-O-group in which thecycloalkyl group is as previously defined, for example C₃₋₄cycloalkoxy(or —O—C₃₋₄cycloalkyl) means a hydrocarbon ring containing from 3 to 4carbon atoms, linked to an O atom e.g. and

The term “halo” or “halogeno” refers to fluoro, chloro, bromo and iodo.

The term “heterocyclyl”, “heterocyclic” or “heterocycle” means anon-aromatic saturated or partially saturated monocyclic, fused,bridged, or spiro bicyclic heterocyclic ring system(s). The termheterocyclyl includes both monovalent species and divalent species.Monocyclic heterocyclic rings contain from about 3 to 12 (suitably from3 to 7, most suitably from 5 to 6) ring atoms, with from 1 to 5(suitably 1, 2 or 3) heteroatoms selected from nitrogen, oxygen orsulfur in the ring. Bicyclic heterocycles contain from 7 to 17 memberatoms, suitably 7 to 12 member atoms, in the ring. Bicyclic heterocyclescontain from about 7 to about 17 ring atoms, suitably from 7 to 12 ringatoms. Bicyclic heterocyclic(s) rings may be fused, spiro, or bridgedring systems. Examples of heterocyclic groups include cyclic ethers suchas oxiranyl, oxetanyl, tetrahydrofuranyl, dioxanyl, and substitutedcyclic ethers. Heterocycles containing nitrogen include, for example,azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrotriazinyl,tetrahydropyrazolyl, and the like. Typical sulfur containingheterocycles include tetrahydrothienyl, dihydro-1,3-dithiol,tetrahydro-2H-thiopyran, and hexahydrothiepine. Other heterocyclesinclude dihydro-oxathiolyl, tetrahydro-oxazolyl, tetrahydro-oxadiazolyl,tetrahydrod ioxazolyl, tetrahydro-oxath iazolyl, hexahydrotriazinyl,tetrahydro-oxazinyl, morpholinyl, thiomorpholinyl,tetrahydropyrimidinyl, dioxolinyl, octahydrobenzofuranyl,octahydrobenzimidazolyl, and octahydrobenzothiazolyl. For heterocyclescontaining sulfur, the oxidized sulfur heterocycles containing SO or SO₂groups are also included. Examples include the sulfoxide and sulfoneforms of tetrahydrothienyl and thiomorpholinyl such as tetrahydrothiene1,1-dioxide and thiomorpholinyl 1,1-dioxide. A suitable value for aheterocyclyl group which bears 1 or 2 oxo (═O) or thioxo (═S)substituents is, for example, 2-oxopyrrolidinyl, 2-thioxopyrrolidinyl,2-oxoimidazolidinyl, 2-thioxoimidazolidinyl, 2-oxopiperidinyl,2,5-dioxopyrrolidinyl, 2,5-dioxoimidazolidinyl or 2,6-dioxopiperidinyl.Particular heterocyclyl groups are saturated monocyclic 3 to 7 memberedheterocyclyls containing 1, 2 or 3 heteroatoms selected from nitrogen,oxygen or sulfur, for example azetidinyl, tetrahydrofuranyl,tetrahydropyranyl, pyrrolidinyl, morpholinyl, tetrahydrothienyl,tetrahydrothienyl 1,1-dioxide, thiomorpholinyl, thiomorpholinyl1,1-dioxide, piperidinyl, homopiperidinyl, piperazinyl orhomopiperazinyl. As the skilled person would appreciate, any heterocyclemay be linked to another group via any suitable atom, such as via acarbon or nitrogen atom. However, reference herein to piperidino ormorpholino refers to a piperidin-1-yl or morpholin-4-yl ring that islinked via the ring nitrogen.

A “carbon-linked heterocyclyl” means a heretocycle group as definedabove that is connected via a carbon atom, rather than a heteroatom suchas nitrogen.

By “spirocyclic ring systems” it is meant a compound which at least tworings which have only one atom in common and are not linked by a bridge.

By “fused ring systems” it is meant a compound in which two rings sharetwo adjacent atoms. In other words, the rings share one covalent bond.

By “bridged ring systems” is meant ring systems in which two rings sharemore than two atoms, see for example Advanced Organic Chemistry, byJerry March, 4^(th) Edition, Wiley Interscience, pages 131-133, 1992.Examples of bridged heterocyclyl ring systems include,aza-bicyclo[2.2.1]heptane, 2-oxa-5-azabicyclo[2.2.1]heptane,aza-bicyclo[2.2.2]octane, aza-bicyclo[3.2.1]octane and quinuclidine.

The term “heteroaryl” or “heteroaromatic” means an aromatic mono-, bi-,or polycyclic ring incorporating one or more (for example 1-4,particularly 1, 2 or 3) heteroatoms selected from nitrogen, oxygen orsulfur. The term heteroaryl includes both monovalent species anddivalent species. Examples of heteroaryl groups are monocyclic andbicyclic groups containing from five to twelve ring members, and moreusually from five to ten ring members. The heteroaryl group can be, forexample, a 5- or 6-membered monocyclic ring or a 9- or 10-memberedbicyclic ring, for example a bicyclic structure formed from fused fiveand six membered rings or two fused six membered rings. Each ring maycontain up to about four heteroatoms typically selected from nitrogen,sulfur and oxygen. Typically the heteroaryl ring will contain up to 3heteroatoms, more usually up to 2, for example a single heteroatom. Inone embodiment, the heteroaryl ring contains at least one ring nitrogenatom. The nitrogen atoms in the heteroaryl rings can be basic, as in thecase of an imidazole or pyridine, or essentially non-basic as in thecase of an indole or pyrrole nitrogen. In general the number of basicnitrogen atoms present in the heteroaryl group, including any aminogroup substituents of the ring, will be less than five.

Examples of heteroaryl include furyl, pyrrolyl, thienyl, oxazolyl,isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl,thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl,pyrazinyl, 1,3,5-triazenyl, benzofuranyl, indolyl, isoindolyl,benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl,benzothiazolyl, indazolyl, purinyl, benzofurazanyl, quinolyl,isoquinolyl, quinazolinyl, quinoxalinyl, cinnolinyl, pteridinyl,naphthyridinyl, carbazolyl, phenazinyl, benzisoquinolinyl,pyridopyrazinyl, thieno[2,3-b]furanyl, 2H-furo[3,2-b]-pyranyl,5H-pyrido[2,3-d]-o-oxazinyl, 1H-pyrazolo[4,3-d]-oxazolyl,4H-imidazo[4,5-d]thiazolyl, pyrazino[2,3-d]pyridazinyl,imidazo[2,1-b]thiazolyl, imidazo[1,2-b][1,2,4]triazinyl. “Heteroaryl”also covers partially aromatic bi- or polycyclic ring systems wherein atleast one ring is an aromatic ring and one or more of the other ring(s)is a non-aromatic, saturated or partially saturated ring, provided atleast one ring contains one or more heteroatoms selected from nitrogen,oxygen or sulfur. Examples of partially aromatic heteroaryl groupsinclude for example, tetrahydroisoquinolinyl, tetrahydroquinolinyl,2-oxo-1,2,3,4-tetrahydroquinolinyl, dihydrobenzthienyl,dihydrobenzfuranyl, 2,3-dihydro-benzo[1,4]dioxinyl, benzo[1,3]dioxolyl,2,2-dioxo-1,3-dihydro-2-benzothienyl, 4,5,6,7-tetrahydrobenzofuranyl,indolinyl, 1,2,3,4-tetrahydro-1,8-naphthyridinyl,1,2,3,4-tetrahydropyrido[2,3-b]pyrazinyl and3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl.

Examples of five membered heteroaryl groups include but are not limitedto pyrrolyl, furanyl, thienyl, imidazolyl, furazanyl, oxazolyl,oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl,pyrazolyl, triazolyl and tetrazolyl groups.

Examples of six membered heteroaryl groups include but are not limitedto pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl and triazinyl.

A bicyclic heteroaryl group may be, for example, a group selected from:

a benzene ring fused to a 5- or 6-membered ring containing 1, 2 or 3ring heteroatoms;a pyridine ring fused to a 5- or 6-membered ring containing 1, 2 or 3ring heteroatoms;a pyrimidine ring fused to a 5- or 6-membered ring containing 1 or 2ring heteroatoms;a pyrrole ring fused to a 5- or 6-membered ring containing 1, 2 or 3ring heteroatoms;a pyrazole ring fused to a 5- or 6-membered ring containing 1 or 2 ringheteroatoms;a pyrazine ring fused to a 5- or 6-membered ring containing 1 or 2 ringheteroatoms;an imidazole ring fused to a 5- or 6-membered ring containing 1 or 2ring heteroatoms;an oxazole ring fused to a 5- or 6-membered ring containing 1 or 2 ringheteroatoms;an isoxazole ring fused to a 5- or 6-membered ring containing 1 or 2ring heteroatoms;a thiazole ring fused to a 5- or 6-membered ring containing 1 or 2 ringheteroatoms;an isothiazole ring fused to a 5- or 6-membered ring containing 1 or 2ring heteroatoms;a thiophene ring fused to a 5- or 6-membered ring containing 1, 2 or 3ring heteroatoms;a furan ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ringheteroatoms;a cyclohexyl ring fused to a 5- or 6-membered heteroaromatic ringcontaining 1, 2 or 3 ring heteroatoms; anda cyclopentyl ring fused to a 5- or 6-membered heteroaromatic ringcontaining 1, 2 or 3 ring heteroatoms.

Particular examples of bicyclic heteroaryl groups containing a sixmembered ring fused to a five membered ring include but are not limitedto benzfuranyl, benzthiophenyl, benzimidazolyl, benzoxazolyl,benzisoxazolyl, benzthiazolyl, benzisothiazolyl, isobenzofuranyl,indolyl, isoindolyl, indolizinyl, indolinyl, isoindolinyl, purinyl(e.g., adeninyl, guaninyl), indazolyl, benzodioxolyl andpyrazolopyridinyl groups.

Particular examples of bicyclic heteroaryl groups containing two fusedsix membered rings include but are not limited to quinolinyl,isoquinolinyl, chromanyl, thiochromanyl, chromenyl, isochromenyl,chromanyl, isochromanyl, benzodioxanyl, quinolizinyl, benzoxazinyl,benzodiazinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl,phthalazinyl, naphthyridinyl and pteridinyl groups.

The term “aryl” means a cyclic or polycyclic aromatic ring having from 5to 12 carbon atoms. The term aryl includes both monovalent species anddivalent species.

Examples of aryl groups include, but are not limited to, phenyl,biphenyl, naphthyl and the like.

In particular embodiment, an aryl is phenyl.

The term “optionally substituted” refers to either groups, structures,or molecules that are substituted and those that are not substituted.

Where optional substituents are chosen from “one or more” groups it isto be understood that this definition includes all substituents beingchosen from one of the specified groups or the substituents being chosenfrom two or more of the specified groups.

The phrase “compound of the invention” means those compounds which aredisclosed herein, both generically and specifically.

Compounds of the Invention

In one aspect, the present invention relates to compounds of formula (I)shown below, or a pharmaceutically acceptable salt thereof:

X—Y—Z  (I)

wherein:X is selected from:

whereinQ₁ is selected from NH, N—C₁₋₄alkyl, O or S;Q_(2a) is selected from N or CR_(2a);Q_(2b) is selected from N or CR_(2b);Q_(2c) is selected from N or CR_(2c);Q_(2d) is selected from N or CR_(2d);Q₃ is selected from N or CR_(1b);Q₃ is selected from N or CR_(1x);subject to the proviso that no more than 3 of Q₁, Q_(2a), Q_(2b),Q_(2c), Q_(2d), Q₃ and Q₄ are nitrogen;R_(1a) is selected from:

-   -   (i) C₁₋₄alkyl or C₁₋₄alkoxy, each of which being optionally        substituted by halo, cyano, hydroxy, C₃₋₆cycloalkyl, C₁₋₄alkoxy,        C₁₋₄haloalkoxy, aryl or heteroaryl; or    -   (ii) a group of the formula:

—(CR_(1c)R_(1d))_(p)—NR_(1e)R_(1f);

wherein

-   -   p is an integer selected from 0, 1, 2 or 3    -   R_(1c) and R_(1d) are independently selected from:        -   (i) hydrogen (including deuterium),        -   (ii) C₁₋₆alkyl which is optionally substituted by one more            substituents selected from cyano, oxo, hydroxy, C₁₋₄alkoxy,            halo, C₁₋₄haloalkoxy, C₃₋₆cycloalkyl, —O—C₃₋₆cycloalkyl,            NR_(1ca)R_(1da) or —S(O)₀₋₂R_(1ca)R_(1da), wherein R_(1ca)            and R_(1da) are H or C₁₋₂alkyl; and wherein C₃₋₆cycloalkyl            and —O—C₃₋₆cycloalkyl are optionally further substituted            with halo, cyano or hydroxy;        -   (iii) C₃₋₄cycloalkyl or 3 to 5 membered heterocyclyl, each            of which is optionally substituted by C₁₋₄alkyl,            C₁₋₄haloalkyl, cyano, hydroxy, C₁₋₂alkoxy, halo,            C₁₋₂haloalkoxy, NR_(1ca)R_(1da) or —S(O)₀₋₂R_(1ca)R_(1da),            wherein R_(1ca) and R_(1da) are H or C₁₋₂alkyl; and;        -   (iv) or R_(1c) and R_(1d) are linked together such that,            together with the carbon atom to which they are attached,            they form a 3- to 6-membered cycloalkyl or heterocyclic            ring, or a spirocyclic ring system, each of which is            optionally substituted by one or more substituents selected            from C₁₋₂alkyl, C₁₋₂haloalkyl, cyano, hydroxy, C₁₋₂alkoxy,            halo, C₁₋₂haloalkoxy, NR_(1ca)R_(1da) or            —S(O)₀₋₂R_(1ca)R_(1da), wherein R_(1ca) and R_(1da) are H or            C₁₋₂alkyl;    -   R_(1e) and R_(1f) are each independently selected from:        -   (i) hydrogen (including deuterium);        -   (ii) C₁₋₆alkyl which is optionally substituted by one more            substituents selected from cyano, oxo, hydroxy, C₁₋₂alkoxy,            halo, C₁₋₂haloalkoxy, NR_(1ea)R_(1fa) or            —S(O)₀₋₂R_(1ea)R_(1fa), wherein R_(1ea) and R_(1fa) are H or            C₁₋₂alkyl;        -   (iii) a group with the formula:

—(CR_(1g)R_(1h))_(q)-T₁

-   -   -   -   wherein:            -   q is 0, 1, 2, 3, 4, 5 or 6;            -   R_(1g) and R_(1h) are independently selected from:                -   a) hydrogen;                -   b) C₁₋₆alkyl which is optionally substituted by one                    more substituents selected from cyano, hydroxy,                    C₁₋₄alkoxy, halo, C₁₋₄haloalkoxy, —O—C₃₋₆                    cycloalkyl, NR_(1ga)R_(1ha) or                    —S(O)₀₋₂R_(1ga)R_(1ha), wherein R_(1ga) and R_(1ha)                    are H or C₁₋₂alkyl; and wherein —O—C₃₋₆cycloalkyl is                    optionally substituted with halo, cyano or hydroxy;                -   c) an aryl-C₁₋₆alkyl, heteroarylC₁₋₆alkyl,                    C₃₋₆-cycloalkyl or C₃₋₆cycloalkylC₁₋₆alkyl group,                    each of which is optionally substituted by one or                    more substituents selected from C₁₋₂alkyl, cyano,                    C₁₋₂haloalkyl, hydroxy, C₁₋₂alkoxy, halo,                    C₁₋₂-haloalkoxy, NR_(1ga)R_(1ha) or                    —S(O)₀₋₂R_(1ga)R_(1ha), wherein R_(1ga) and R_(1ha)                    are H or C₁₋₂alkyl; or                -   d) or R_(1g) and R_(1h) are optionally linked                    together such that, together with the carbon atom to                    which they are attached, they form a 3- to                    6-membered cycloalkyl or heterocyclic ring which is                    optionally substituted by one or more substituents                    selected from C₁₋₂alkyl, cyano, C₁₋₂haloalkyl,                    hydroxy, C₁₋₂alkoxy, halo, C₁₋₂haloalkoxy,                    NR_(1ga)R_(1ha) or —S(O)₀₋₂R_(1ga)R_(1ha), wherein                    R_(1ga) and R_(1ha) are H or C₁₋₂alkyl;            -   and T₁ is selected from hydrogen, cyano, hydroxy,                NR_(1t)R_(2t) or —S(O)₀₋₂R_(1t)R_(2t) (wherein R_(1t)                and R_(2t) are H or C₁₋₄alkyl), C₃₋₈cycloalkyl,                C₂₋₃alkenyl, C₂₋₃alkynyl, aryl, heterocyclyl,                heteroaryl, a spirocyclic carbocyclic or heterocyclic                ring system, a bridged C₃₋₈cycloalkyl, a bridged                bicyclic C₅₋₁₂cycloalkyl, or a bridged heterocyclic ring                system, each of which is optionally substituted by one                or more substituents selected from C₁₋₂alkyl,                C₁₋₂-haloalkyl, cyano, hydroxy, C₁₋₂alkoxy, halo,                C₁₋₂-haloalkoxy, NR_(3t)R_(4t) or —S(O)₀₋₂R_(3t)R_(4t),                wherein R_(3t) and R_(4t) are H or C₁₋₂alkyl;

        -   (iv) or R_(1e) and R_(1f) are linked such that, together            with the nitrogen atom to which they are attached, they form            a mono- or bicyclic-heterocyclic ring, which is optionally            substituted by one or more substituents selected from            C₁₋₄alkyl, C₁₋₄haloalkyl, cyano, hydroxy, C₁₋₄alkoxy, halo,            C₁₋₄haloalkoxy, NR_(1i)R_(1j) or —S(O)₀₋₂R_(1i)R_(1j),            wherein R_(1i) and R_(1j) are H or C₁₋₄alkyl, and/or the            mono- or bicyclic hetereocyclic ring formed by R_(1e) and            R_(1f) is optionally spiro-fused to a C₃₋₆cycloalkyl or a            heterocyclic ring, which in turn is optionally substituted            by one or more substituents selected from C₁₋₄alkyl,            C₁₋₄haloalkyl, cyano, hydroxy, C₁₋₄alkoxy, halo,            C₁₋₄haloalkoxy, NR_(1i)R_(1j) or —S(O)₀₋₂R_(1i)R_(1j),            wherein R_(1i) and R_(1j) are H or C₁₋₄alkyl;            R_(1b) is selected from hydrogen, cyano, halo or C₁₋₃ alkyl;            R_(1x) is selected from hydrogen, cyano, halo or C₁₋₃ alkyl;            R_(2a), R_(2b), R_(2c) and R_(2d) are independently selected            from hydrogen, cyano, halo or a group of the formula:

-L_(2a)-L_(2b)-Q₂

wherein

-   -   L_(2a) is absent or C₁₋₃alkylene optionally substituted by C₁₋₂        alkyl or oxo;    -   L_(2b) is absent or selected from O, S, SO, SO₂, N(Rn), C(O),        C(O)O, OC(O), C(O)N(R_(n)), N(R_(n))C(O), N(R_(n))C(O)N(R_(o)),        S(O)₂N(R_(n)), or N(R_(n))SO₂, wherein R_(n) and R_(o) are each        independently selected from hydrogen or C₁₋₂alkyl; and    -   Q₂ is hydrogen, cyano, C₁₋₆alkyl, C₃₋₆cycloalkyl, aryl,        heterocyclyl or heteroaryl, each of which is optionally        substituted by one or more substituents selected from halo,        trifluoromethyl, trifluoromethoxy, amino, cyano, hydroxy, amino,        carboxy, carbamoyl, sulphamoyl, C₁₋₄alkyl, NR_(p)R_(q), OR_(p),        C(O)R_(p), C(O)OR_(p), OC(O)R_(p), C(O)N(R_(p))R_(q),        N(R_(f))C(O)R_(p), S(O)_(y)R_(p) (where y is 0, 1 or 2),        SO₂N(R_(p))R_(q), N(Rr)SO₂R_(p) or (CH₂)_(z)NR_(p)R_(q) (where z        is 1, 2 or 3), wherein R_(p) and R_(q) are each independently        selected from hydrogen or C₁₋₄alkyl;        Y is selected from:

wherein:

-   -   R_(3a1), R_(3b1), R_(3c1), R_(3d1), R_(3e1), R_(3f1), R_(3g1),        R_(3h1), R_(3i1), R_(3j1), R_(3k1), R_(3l1), R_(3m1), R_(3n1),        R_(3o1), R_(3p1), R_(3q1), R_(3r1) and R_(3s1) are independently        selected from hydrogen (including deuterium), C₁₋₆alkyl, C₃₋₄        cycloalkyl, hydroxy, and halo; and wherein C₁₋₆alkyl, or C₃₋₄        cycloalkyl is optionally substituted with one or more        substituents selected from halo, amino, cyano, and hydroxy;    -   R_(3a2), R_(3b2), R_(3c2), R_(3d2), R_(3e2), R_(3f2), R_(3g2),        R_(3h2), R_(3i2), R_(3j2), R_(3k2), R_(3l2), R_(3m2), R_(3n2),        R_(3o2), R_(3p2), R_(3q2), R_(3r2) and R_(3s2) are hydrogen or        halo;    -   with the proviso that R_(3a1), R_(3b1), R_(3i1), R_(3l1),        R_(3o1), R_(3r1), R_(3a2), R_(3b2), R_(3i2), R_(3l2), R_(3o2)        and R_(3s1) cannot be halo when n=1 or when n=2 and the carbon        atom to which they are attached is linked to an oxygen or        nitrogen atom;    -   or R_(3a1) and R_(3a2), R_(3b1) and R_(3b2), R_(3c1) and        R_(3c2), R_(3d1) and R_(3d2), R_(3e1) and R_(3e2), R_(3f1) and        R_(3f2), R_(3g1) and R_(3g2), R_(3h1) and R_(3h2), R_(3i1) and        R_(3i2), R_(3j1) and R_(3j2), R_(3k1) and R_(3k2), R_(3l1) and        R_(3l2), R_(3m1) and R_(3m2), R_(3n1) and R_(3n2), R_(3o1) and        R_(3o2), R_(3p1) and R_(3p2), R_(3q1) and R_(3q2), or R_(3r1)        and R_(3r2) or R_(3s1) and R_(3s2) may be linked such that,        together with the carbon atom to which they are attached, they        form a spiro-fused C₃₋₄cycloalkyl which is optionally        substituted with one or more substituents selected from halo,        methyl, amino, cyano, and hydroxy;    -   n is 0, 1 or 2        Z is selected from one of the following structures:

wherein:

-   -   B₁ is A₅, wherein A₅ is selected from CR₁₆ and N, wherein R₁₆ is        selected from hydrogen, halo, cyano, C₁₋₄ alkyl, C₂₋₄ alkenyl,        C₂₋₄ alkynyl, a 5- or 6-membered heteroaryl, C₁₋₄ alkoxy,        C₁₋₄haloalkyl, C₁₋₄haloalkoxy, C₃₋₄cycloalkyl, a 3- to        4-membered heterocyclyl and C₃₋₄cycloalkoxy;    -   B₂ is A₆, wherein A₆ is selected from N or CR₁₇, wherein R₁₇,        R_(H2), R_(H4) and R_(H5) are selected from hydrogen, hydroxy,        halo, cyano, C₁₋₅ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄        haloalkoxy, C₂₋₄ alkenyl, C₂₋₄ alkynyl, phenyl, a 5- or        6-membered or heteroaryl, C₃₋₆cycloalkyl, —O—C₃₋₆cycloalkyl,        heterocyclyl, —O-heterocyclyl (carbon-linked),        —(OCH₂CH₂)_(m)—NR_(q)R_(r), —(OCH₂CH₂)_(m)—OCH₃ wherein m is an        integer from 1 to 6, NR_(q)R_(r), —C(O)—NR_(q)R_(r),        —C(O)OR_(q),        -   wherein R_(q) and R_(r) are each independently hydrogen,            C₁₋₅ alkyl, C₃₋₆cycloalkyl, a 3- to 6-membered carbon-linked            heterocyclyl, or R_(q) and R_(r) are linked together such            that, together with the nitrogen atom to which they are            attached, they form a 3- to 6-membered heterocyclic ring;        -   wherein any C₁₋₅alkyl, C₁₋₄ alkoxy, C₂₋₄alkenyl,            C₂₋₄alkynyl, phenyl, 5- or 6-membered or heteroaryl,            C₃₋₆cycloalkyl, —O—C₃₋₆cycloalkyl, heterocyclyl or —O—            heterocyclyl (carbon-linked) is optionally further            substituted by one or more substituents selected from            C₁₋₂alkyl, cyano, C₁₋₂haloalkyl, hydroxy, C₁₋₂alkoxy, halo,            C₁₋₂haloalkoxy, NR_(1ea)R_(1fa) or —S(O)₀₋₂R_(1ea)R_(1fa),            wherein R_(1ea) and R_(1f) are H or C₁₋₂alkyl;

B₃ is N or CR_(Z1), wherein R_(Z1) is selected from hydrogen, C₁₋₄alkyl,cyano, halo, C₁₋₄haloalkyl, C₁₋₄haloalkoxy, C₁₋₄alkoxy, C₃₋₆cycloalkyland —O—C₃₋₆cycloalkyl, wherein C₃₋₆cycloalkyl and —O—C₃₋₆cycloalkyl areoptionally substituted by one or more of halo, methyl or methoxy;

-   -   B₄ is selected from C or N;    -   B₅ is selected from CR_(zi1b) or NR_(B5N), wherein:        -   R_(Zi1b) is selected from hydrogen, C₁₋₄alkyl, cyano, halo,            NH₂ and C₁₋₄alkoxy; and        -   R_(B5N) is selected from hydrogen or C₁₋₄alkyl;    -   B₇ is N, NR_(Z2N) or CR_(Z2), wherein R_(Z2) is selected from        hydrogen, C₁₋₄alkyl, cyano, halo, NH₂ and C₁₋₄alkoxy; and        R_(Z2N) is selected from hydrogen or C₁₋₄alkyl;    -   B₈ is selected from C or N;    -   with the proviso that no more than four of B₁ to B₈ are N.

Y₂ is A₇, wherein A₇ is selected from CR₁₈ and N; wherein R₁₈ isselected from hydrogen, halo, cyano, C₁₋₄ alkyl, C₁₋₄ alkoxy,C₁₋₄haloalkyl, C₁₋₄haloalkoxy, C₃₋₄cycloalkyl, a 3- to 4-memberedheterocyclyl and C₃₋₄cycloalkoxy;Y₃ is N or CR_(z1a) wherein R_(Z1a), is selected from hydrogen, hydroxy,C₁₋₄alkyl, cyano, halo, C₁₋₄ haloalkyl, C₁₋₄haloalkoxy, C₁₋₄alkoxy,C₃₋₆cycloalkyl and —O—C₃₋₆cycloalkyl, wherein C₃₋₆ cycloalkyl and—O—C₃₋₆cycloalkyl are optionally substituted by one or more of halo,methyl or methoxy;

Y₄ is C or N

Y₅ is C—R_(Y5) or NR_(Y5N), wherein:

-   -   R_(Y5) is selected from hydrogen, C₁₋₄alkyl, cyano, halo, NH₂        and C₁₋₄alkoxy;    -   R_(Y5N) is selected from hydrogen or C₁₋₄alkyl;        Y₆ is C—R_(Zi2e) or N, wherein R_(Zi2e) is selected from        hydrogen, C₁₋₄alkyl, cyano, halo, NH₂ and C₁₋₄alkoxy        Y₇ is O, S, CR_(Z2a) or N, wherein R_(Z2a) is selected from        hydrogen, C₁₋₄alkyl, cyano, halo, NH₂ and C₁₋₄alkoxy;

Y₈ Is C or N;

Y₉ is CR_(Z3a) or N; wherein

-   -   R_(Z3a) is selected from hydrogen, C₁₋₄alkyl, cyano, halo, NH₂        and C₁₋₄alkoxy;    -   with the proviso that no more than four of Y₁ to Y₈ are N.

-   -   X₁ is N or C—R_(Z9), wherein R_(Z9) is selected from hydrogen,        halo, cyano, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄alkoxy, C₁₋₄        haloalkoxy;    -   X₂ is selected from N or CR₄ wherein:        -   R₄ is selected from hydrogen, halo, cyano, C₁₋₄ alkyl, C₁₋₄            haloalkyl, C₁₋₄alkoxy, C₁₋₄ haloalkoxy (e.g. hydrogen, halo,            cyano and methyl);    -   X₃ is N;    -   X₄ is N or C;    -   X₅ is selected from N, CR₅ and CR_(X5a)R_(X5b) wherein:        -   R₅ is selected from hydrogen, halo, cyano, C₁₋₄ alkyl, C₁₋₄            haloalkyl, C₁₋₄alkoxy, C₁₋₄ haloalkoxy (e.g. hydrogen, halo,            cyano and methyl);        -   R_(X5a) and R_(X5b) are independently selected from            hydrogen, halo, cyano, C₁₋₄ alkyl, C₁₋₄ haloalkyl,            C₁₋₄alkoxy, C₁₋₄ haloalkoxy (e.g. hydrogen, halo, cyano and            methyl);    -   either:        -   X₆ is A₁ and X₇ is A₂; or        -   X₆ is A₈ and X₇ is A₉ or A₁₁, wherein:        -   A₁ is selected from CR₁₂ and N; wherein            -   R₁₂ is selected from selected from hydrogen, halo,                cyano, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄alkoxy and C₁₋₄                haloalkoxy (e.g. hydrogen, halo, cyano and C₁₋₄ alkyl);        -   A₂ is selected from CR₁₃ and N, wherein            -   R₁₃ selected from hydrogen, halo, cyano, C₁₋₄ alkyl,                C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy (e.g.                hydrogen, halo, cyano, methoxy and methyl);        -   A₈ is selected from CR₁₉R₂₀ and NR₂₁; wherein            -   R₁₉ and R₂₀ are independently selected from hydrogen,                halo, cyano, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄alkoxy,                C₁₋₄ haloalkoxy (e.g hydrogen, halo, cyano and C₁₋₄                alkyl);            -   R₂₁ is hydrogen or C₁₋₄alkyl.        -   A₉ is selected from CR₂₂R₂₃ and NR₂₄;            -   wherein R₂₂ and R₂₃ are independently selected from                selected from hydrogen, halo, cyano, C₁₋₄ alkyl, C₁₋₄                haloalkyl, C₁₋₄alkoxy, C₁₋₄ haloalkoxy (e.g. hydrogen,                halo, cyano and methyl);            -   R₂₄ is selected from hydrogen or C₁₋₄alkyl        -   A₁₁ is selected from CR₂₈R₂₉ and NR₃₀;            -   R₂₉ and R₂₉ are selected from hydrogen, halo, methoxy                and methyl;            -   R₃₀ is selected from hydrogen or C₁₋₄alkyl.    -   X₈ is selected from CR₆, N or CR_(X6a)R_(X6b);        -   wherein R₆ is selected from hydrogen, halo, cyano, C₁₋₄            alkyl, C₁₋₄ haloalkyl, C₁₋₄alkoxy and C₁₋₄ haloalkoxy;        -   R_(X6a) and R_(X6b) are each independently selected from            hydrogen, halo, cyano, C₁₋₄ alkyl, C₁₋₄ haloalkyl,            C₁₋₄alkoxy and C₁₋₄ haloalkoxy;    -   X₉ is N or C;    -   with the proviso that no more than four of X₂ to X₉ are N.        (iv)

Z₁₀ is N or C—R_(Z10), wherein R_(Z10) is selected from hydrogen, halo,cyano, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄alkoxy, C₁₋₄ haloalkoxy;Z₁₁ is N or C—R_(Z11), wherein R_(Z11) is selected from hydrogen, halo,cyano, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄alkoxy, C₁₋₄ haloalkoxy;Z₁₂ is N or C—R_(Z12), wherein R_(Z12) is selected from hydrogen, halo,cyano, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄alkoxy, C₁₋₄ haloalkoxy;Z₁₃ is N or C—R_(Z13), wherein R_(Z13) is selected from hydrogen, halo,cyano, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄alkoxy, C₁₋₄ haloalkoxy;Z₁₄ is N or C—R_(Z14), wherein R_(Z14) is selected from hydrogen, halo,cyano, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄alkoxy, C₁₋₄ haloalkoxy;Z₁₅ is N or C—R_(Z15), wherein R_(Z15) is selected from hydrogen, halo,cyano, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄alkoxy, C₁₋₄ haloalkoxy;Z₁₆ is N or C—R_(Z16), wherein R_(Z16) is selected from hydrogen, halo,cyano, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄alkoxy, C₁₋₄ haloalkoxy;with the proviso that no more than three of Z₁₀ to Z₁₆ are N;(v)

-   -   Q₇ is CR₇ or N;    -   Q₈ is CR₈ or N;    -   Q₉ is CR₉ or N;    -   Q₁₀ is CR₁₀ or N;    -   Q₁₁ is CR₁₁ or N;    -   Q_(11a) is NR_(11N) or CR_(11a)R_(11b);        wherein R₇, R₈, R₉, R₁₀, R₁₁, R_(11a) and R_(11b) are each        independently selected from hydrogen, NH₂, halo, cyano, C₁₋₄        alkoxy, C₁₋₄ haloalkoxy, C₁₋₆ alkyl, —CH₂OCH₃, —CH₂SO₂CH₃,        —SO₂CH₃, —NHC(O)CH₃ and —C(O)NR_(v1)R_(v2), wherein R_(v1) and        R_(v2) are independently selected from hydrogen and methyl and;        and R_(11N) is selected from hydrogen, NH₂, halo, cyano, and        C₁₋₆ alkyl;        or    -   R₉ and R₁₀ may be linked together such that, together to the        atoms to which they are attached, they form a fused 5- or        6-membered saturated or unsaturated ring system, or R₁₀ and R₁₁        may be linked together such that, together to the atoms to which        they are attached, they form a fused 5- or 6-membered saturated        or unsaturated ring system, wherein either of the fused 5- or        6-membered saturated or unsaturated ring system may be        optionally substituted by one or more substituents selected from        C₁₋₂alkyl, cyano, C₁₋₂haloalkyl, hydroxy, C₁₋₂alkoxy, halo,        C₁₋₂haloalkoxy, NR_(1ia)R_(1ja) or —S(O)₀₋₂R_(1ia)R_(1ja),        wherein R_(1ia) and R_(1ja) are H or C₁₋₂alky;        with the proviso that no more than three of Q₇ to Q₁₁ are N.

In another aspect, the present invention relates to compounds of formula(I) shown below, or a pharmaceutically acceptable salt thereof:

X—Y—Z  (I)

wherein:X is selected from:

whereinQ₁ is selected from NH, N—C₁₋₄alkyl, O or S;Q_(2a) is selected from N or CR_(2a);Q_(2a) is selected from N or CR_(2a);Q_(2b) is selected from N or CR_(2b);Q_(2d) is selected from N or CR_(2d);Q₃ is selected from N or CR_(1b);Q₄ is selected from N or CR_(1x);subject to the proviso that no more than 3 of Q₁, Q_(2a), Q_(2b),Q_(2c), Q_(2d), Q₃ and Q₄ are nitrogen;R_(1a) is selected from:

-   -   (i) C₁₋₄alkyl or C₁₋₄alkoxy, each of which being optionally        substituted by halo, cyano, hydroxy, C₃₋₆cycloalkyl, 3 to 6        membered heterocyclyl, C₁₋₄alkoxy, C₁₋₄haloalkoxy, aryl or        heteroaryl; or    -   (ii) a group of the formula:

—(CR_(1c)R_(1d))_(p)—NR_(1e)R_(1f);

-   -   wherein        -   p is an integer selected from 0, 1, 2 or 3        -   R_(1c) and R_(1d) are independently selected from:            -   (i) hydrogen (including deuterium),            -   (ii) C₁₋₆alkyl which is optionally substituted by one                more substituents selected from cyano, oxo, hydroxy,                C₁₋₄alkoxy, halo, C₁₋₄haloalkoxy, C₃₋₆cycloalkyl,                —O—C₃₋₆cycloalkyl, NR_(1ca)R_(1da) or                —S(O)₀₋₂R_(1ca)R_(1da), wherein R_(1ca) and R_(1da) are                H or C₁₋₂alkyl; and wherein C₃₋₆cycloalkyl and                —O—C₃₋₆cycloalkyl are optionally further substituted                with halo, cyano or hydroxy;            -   (iii) C₃₋₄cycloalkyl or 3 to 5 membered heterocyclyl,                each of which is optionally substituted by C₁₋₄alkyl,                C₁₋₄haloalkyl, cyano, hydroxy, C₁₋₂alkoxy, halo,                C₁₋₂haloalkoxy, NR_(1ca)R_(1da) or                —S(O)₀₋₂R_(1ca)R_(1da), wherein R_(1ca) and R_(1da) are                H or C₁₋₂alkyl;            -   (iv) or R_(1c) and R_(1d) are linked together such that,                together with the carbon atom to which they are                attached, they form a 3- to 6-membered cycloalkyl or                heterocyclic ring, or a spirocyclic ring system, each of                which is optionally substituted by one or more                substituents selected from C₁₋₂alkyl, C₁₋₂haloalkyl,                cyano, hydroxy, C₁₋₂alkoxy, halo, C₁₋₂haloalkoxy,                NR_(1ca)R_(1da) or —S(O)₀₋₂R_(1ca)R_(1da), wherein                R_(1ca) and R_(1da) are H or C₁₋₂alkyl;    -   R_(1e) and R_(1f) are each independently selected from:    -   (i) hydrogen (including deuterium);    -   (ii) C₁₋₆alkyl which is optionally substituted by one more        substituents selected from cyano, oxo, hydroxy, C₁₋₂alkoxy,        halo, C₁₋₂haloalkoxy, NR_(1ea)R_(1fa) or —S(O)₀₋₂R_(1ea)R_(1fa),        wherein R_(1ea) and R_(1fa) are H or C₁₋₂alkyl;    -   (iii) a group with the formula:

—(CR_(1g)R_(1h))_(q)-T₁

-   -   -   wherein:            -   q is 0, 1, 2, 3, 4, 5 or 6;            -   R_(1g) and R_(1h) are independently selected from:                -   a) hydrogen;                -   b) C₁₋₆alkyl which is optionally substituted by one                    more substituents selected from cyano, oxo, hydroxy,                    C₁₋₄alkoxy, halo, C₁₋₄haloalkoxy, —O—C₃₋₆cycloalkyl,                    NR_(1ga)R_(1ha) or —S(O)₀₋₂R_(1ga)R_(1ha), wherein                    R_(1ga) and R_(1ha) are H or C₁₋₂alkyl; and wherein                    —O—C₃₋₆cycloalkyl is optionally substituted with                    halo, cyano or hydroxy; or                -   c) an aryl-C₁₋₆alkyl, heteroarylC₁₋₆alkyl,                    C₃₋₆cycloalkyl or C₃₋₆cycloalkylC₁₋₆alkyl group,                    each of which is optionally substituted by one or                    more substituents selected from C₁₋₂alkyl, cyano,                    C₁₋₂haloalkyl, hydroxy, C₁₋₂alkoxy, halo,                    C₁₋₂haloalkoxy, NR_(1ga)R_(1ha) or                    —S(O)₀₋₂R_(1ga)R_(1ha), wherein R_(1ga) and R_(1ha)                    are H or C₁₋₂alkyl;                -   d) or R_(1g) and R_(1h) are optionally linked                    together such that, together with the carbon atom to                    which they are attached, they form a 3- to                    6-membered cycloalkyl or heterocyclic ring which is                    optionally substituted by one or more substituents                    selected from C₁₋₂alkyl, cyano, C₁₋₂haloalkyl,                    hydroxy, C₁₋₂alkoxy, halo, C₁₋₂haloalkoxy,                    NR_(1ga)R_(1ha) or —S(O)₀₋₂R_(1ga)R_(1ha), wherein                    R_(1ga) and R_(1ha) are H or C₁₋₂alkyl;            -   and T₁ is selected from hydrogen, halo, C₁₋₄alkyl,                C₁₋₄haloalkyl, cyano, hydroxy, NR_(1t)R_(2t) or                —S(O)₀₋₂R_(1t)R_(2t) (wherein R_(1t) and R_(2t) are H or                C₁₋₄alkyl), C₃₋₈cycloalkyl, C₂₋₃alkenyl, C₂₋₃alkynyl,                aryl, heterocyclyl, a mono- or bicyclic heteroaryl, a                spirocyclic carbocyclic or heterocyclic ring system, a                bridged C₃₋₈cycloalkyl, a bridged bicyclic                C₅₋₁₂cycloalkyl, or a bridged heterocyclic ring system,                each of which is optionally substituted by one or more                substituents selected from C₁₋₂alkyl, C₁₋₂-haloalkyl,                cyano, hydroxy, C₁₋₂alkoxy, halo, C₁₋₂haloalkoxy, C₃₋₆                cycloalkyl, NR_(3t)R_(4t) or —S(O)₀₋₂R_(3t)R_(4t),                wherein R_(3t) and R_(4t) are H or C₁₋₂alkyl;

    -   (iv) or R_(1e) and R_(1f) are linked such that, together with        the nitrogen atom to which they are attached, they form a mono-        or bicyclic-heterocyclic ring, which is optionally substituted        by one or more substituents selected from C₁₋₄alkyl,        C₁₋₄haloalkyl, C₃₋₆cycloalkyl, cyano, hydroxy, C₁₋₄alkoxy, halo,        C₁₋₄haloalkoxy, NR_(1i)R_(1j) or —S(O)₀₋₂R_(1i)R_(1j), wherein        R_(1i) and R_(1j) are H or C₁₋₄alkyl, and/or the mono- or        bicyclic hetereocyclic ring formed by R_(1e) and R_(1f) is        optionally spiro-fused to a C₃₋₆cycloalkyl or a heterocyclic        ring, which in turn is optionally substituted by one or more        substituents selected from C₁₋₄alkyl, C₁₋₄haloalkyl,        C₃₋₆cycloalkyl, cyano, hydroxy, C₁₋₄alkoxy, halo,        C₁₋₄haloalkoxy, NR_(1i)R_(1j) or —S(O)₀₋₂R_(1i)R_(1j), wherein        R_(1i) and R_(1j) are H or C₁₋₄alkyl;        -   wherein any wherein any alkyl, alkoxy or C₃₋₆cycloalkyl is            further optionally substituted by one or more substituents            selected from cyano, hydroxy, halo, NR_(1k)R_(1l) or            —S(O)₀₋₂R_(1k)R_(1l), wherein R_(1k) and R_(1l) are H or            C₁₋₄alkyl;            R_(1b) is selected from hydrogen, cyano, halo or C₁₋₃ alkyl;            R_(1x) is selected from hydrogen, cyano, halo or C₁₋₃ alkyl;            R_(2a), R_(2b), R_(2c) and R_(2d) are independently selected            from hydrogen, cyano, halo or a group of the formula:

-L_(2a)-L_(2b)-Q₂

wherein

-   -   L_(2a) is absent or C₁₋₃alkylene optionally substituted by C₁₋₂        alkyl or oxo;    -   L_(2b) is absent or selected from O, S, SO, SO₂, N(R_(n)), C(O),        C(O)O, OC(O), C(O)N(R_(n)), N(R_(n))C(O), N(R_(n))C(O)N(R_(o)),        S(O)₂N(R_(n)), or N(R_(n))SO₂, wherein R_(n) and R_(o) are each        independently selected from hydrogen or C₁₋₂alkyl; and    -   Q₂ is hydrogen, cyano, C₁₋₆alkyl, C₃₋₆cycloalkyl, aryl,        heterocyclyl or heteroaryl, each of which is optionally        substituted by one or more substituents selected from halo,        trifluoromethyl, trifluoromethoxy, amino, cyano, hydroxy, amino,        carboxy, carbamoyl, sulphamoyl, C₁₋₄alkyl, NR_(p)R_(q), OR_(p),        C(O)R_(p), C(O)OR_(p), OC(O)R_(p), C(O)N(R_(p))R_(q),        N(R_(r))C(O)R_(p), S(O)_(y)R_(p) (where y is 0, 1 or 2),        SO₂N(R_(p))R_(q), N(R_(r))SO₂R_(p) or (CH₂)_(z)NR_(p)R_(q)        (where z is 1, 2 or 3), wherein R_(p) and R_(q) are each        independently selected from hydrogen or C₁₋₄alkyl;        Y is selected from:

wherein:

-   -   R_(3a1), R_(3b1), R_(3c1), R_(3d1), R_(3e1), R_(3f1), R_(3g1),        R_(3h1), R_(3i1), R_(3j1), R_(3k1), R_(3l1), R_(3m1), R_(3n1),        R_(3o1), R_(3p1), R_(3q1), R_(3r1) and R_(3s1) are independently        selected from hydrogen (including deuterium), C₁₋₆alkyl, C₃₋₄        cycloalkyl, hydroxy, and halo; and wherein C₁₋₆alkyl, or C₃₋₄        cycloalkyl is optionally substituted with one or more        substituents selected from halo, amino, cyano, and hydroxy;    -   R_(3a2), R_(3b2), R_(3c2), R_(3d2), R_(3e2), R_(3f2), R_(3g2),        R_(3h2), R_(3i2), R_(3j2), R_(3k2), R_(3l2), R_(3m2), R_(3n2),        R_(3o2), R_(3p2), R_(3q2), R_(3r2) and R_(3s2) are hydrogen or        halo;    -   with the proviso that R_(3a1), R_(3b1), R_(3i1), R_(3o1),        R_(3r1), R_(3a2), R_(3b2), R_(3i2), R_(3l2), R_(3o2) and R_(3s1)        cannot be halo when n=1 or when n=2 and the carbon atom to which        they are attached is linked to an oxygen or nitrogen atom;    -   or R_(3a1) and R_(3a2), R_(3b1) and R_(3b2), R_(3c1) and        R_(3c2), R_(3d1) and R_(3d2), R_(3e1) and R_(3e2), R_(3f1) and        R_(3f2), R_(3g1) and R_(3g2), R_(3h1) and R_(3h2), R_(3i1) and        R_(3i2), R_(3j1) and R_(3j2), R_(3k1) and R_(3k2), R_(3l1) and        R_(3l2), R_(3m1) and R_(3m2), R_(3n1) and R_(3n2), R_(3o1) and        R_(3o2), R_(3p1) and R_(3p2), R_(3q1) and R_(3q2), or R_(3r1)        and R_(3r2) or R_(3s1) and R_(3s2) may be linked such that,        together with the carbon atom to which they are attached, they        form a spiro-fused C₃₋₄cycloalkyl which is optionally        substituted with one or more substituents selected from halo,        methyl, amino, cyano, and hydroxy;    -   n is 0, 1 or 2        Z is selected from:

-   -   wherein:    -   R₄ is selected from hydrogen, halo, cyano, C₁₋₄ alkyl, C₁₋₄        haloalkyl, C₁₋₄alkoxy, C₁₋₄ haloalkoxy (e.g. hydrogen, halo,        cyano and methyl);    -   R₅ is selected from hydrogen, halo, cyano, C₁₋₄ alkyl, C₁₋₄        haloalkyl, C₁₋₄alkoxy, C₁₋₄ haloalkoxy (e.g. hydrogen, halo,        cyano and methyl);    -   R₆ is selected from hydrogen, halo, cyano, C₁₋₄ alkyl, C₁₋₄        haloalkyl, C₁₋₄alkoxy, C₁₋₄ haloalkoxy (e.g. hydrogen, halo,        cyano and methyl);    -   R₆, R₉, R₁₀ and R₁₁ are independently selected from hydrogen,        NH₂, halo, cyano, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, C₁₋₆ alkyl,        —CH₂OCH₃, —CH₂SO₂CH₃, —SO₂CH₃, —NHC(O)CH₃ and        —C(O)NR_(v1)R_(v2), wherein R_(v1) and R_(v2) are independently        selected from hydrogen and methyl; or    -   R₉ and R₁₀ may be linked together such that, together to the        atoms to which they are attached, they form a fused 5- or        6-membered saturated or unsaturated ring system, or R₁₀ and R₁₁        may be linked together such that, together to the atoms to which        they are attached, they form a fused 5- or 6-membered saturated        or unsaturated ring system, wherein either of the fused 5- or        6-membered saturated or unsaturated ring system may be        optionally substituted by one or more substituents selected from        C₁₋₂alkyl, cyano, C₁₋₂haloalkyl, hydroxy, C₁₋₂alkoxy, halo,        C₁₋₂haloalkoxy, NR_(1ia)R_(1ja) or —S(O)₀₋₂R_(1ia)R_(1ja),        wherein R_(1ia) and R_(1ja) are H or C₁₋₂alky;    -   R₇ and R_(11N) are independently selected from hydrogen, NH₂,        halo, cyano, and C₁₋₆ alkyl;    -   R_(Z1) and R_(Z1a) selected from hydrogen, C₁₋₄alkyl, cyano,        halo, C₁₋₄haloalkyl, C₁₋₄ haloalkoxy, C₁₋₄alkoxy, C₃₋₆cycloalkyl        and —O—C₃₋₆cycloalkyl, wherein C₃₋₆cycloalkyl and        —O—C₃₋₆cycloalkyl are optionally substituted by one or more of        halo, methyl or methoxy;    -   R_(Z2) and R_(Z2a) are selected from hydrogen, C₁₋₄alkyl, cyano,        halo, NH₂ and C₁₋₄alkoxy;    -   R_(Z3a) is selected from hydrogen, C₁₋₄alkyl, cyano, halo, NH₂        and C₁₋₄alkoxy;    -   R_(Zi1b) is selected from hydrogen, C₁₋₄alkyl, cyano, halo, NH₂        and C₁₋₄alkoxy;    -   R_(Zi2e) is selected from hydrogen, C₁₋₄alkyl, cyano, halo, NH₂        and C₁₋₄alkoxy;    -   R_(Y5N) and R_(Z2N) are selected from hydrogen or C₁₋₄alkyl;    -   R_(Z9) is selected from hydrogen, halo, cyano, C₁₋₄ alkyl, C₁₋₄        haloalkyl, C₁₋₄alkoxy, C₁₋₄ haloalkoxy;    -   R_(Z10) is selected from hydrogen, halo, cyano, C₁₋₄ alkyl, C₁₋₄        haloalkyl, C₁₋₄alkoxy, C₁₋₄ haloalkoxy;    -   R_(Z11) is selected from hydrogen, halo, cyano, C₁₋₄ alkyl, C₁₋₄        haloalkyl, C₁₋₄alkoxy, C₁₋₄ haloalkoxy;    -   R_(Z12) is selected from hydrogen, halo, cyano, C₁₋₄ alkyl, C₁₋₄        haloalkyl, C₁₋₄alkoxy, C₁₋₄ haloalkoxy;    -   R_(Z13) is selected from hydrogen, halo, cyano, C₁₋₄ alkyl, C₁₋₄        haloalkyl, C₁₋₄alkoxy, C₁₋₄ haloalkoxy;    -   R_(Z14) is selected from hydrogen, halo, cyano, C₁₋₄ alkyl, C₁₋₄        haloalkyl, C₁₋₄alkoxy, C₁₋₄ haloalkoxy;    -   R_(Z15) is selected from hydrogen, halo, cyano, C₁₋₄ alkyl, C₁₋₄        haloalkyl, C₁₋₄alkoxy, C₁₋₄ haloalkoxy;    -   R_(Z16) is selected from hydrogen, halo, cyano, C₁₋₄ alkyl, C₁₋₄        haloalkyl, C₁₋₄alkoxy, C₁₋₄ haloalkoxy;    -   A₁ is selected from CR₁₂ and N;    -   A₂ is selected from CR₁₃ and N;    -   A₅ is selected from CR₁₆ and N;    -   A₆ is selected from CR₁₇ and N;    -   A₇ is selected from CR₁₈ and N;    -   A₈ is selected from CR₁₉R₂₀ and NR₂₁;    -   A₉ is selected from CR₂₂R₂₃ and NR₂₄;    -   A₁₁ is selected from CR₂₈R₂₉ and NR₃₀;    -   R₁₂ is selected from hydrogen, halo, cyano, C₁₋₄ alkyl, C₁₋₄        haloalkyl, C₁₋₄alkoxy, C₁₋₄ haloalkoxy (e.g. hydrogen, halo,        cyano and C₁₋₄ alkyl);    -   R₁₃ is selected from hydrogen, halo, cyano, C₁₋₄ alkyl, C₁₋₄        haloalkyl, C₁₋₄alkoxy, C₁₋₄ haloalkoxy (e.g. hydrogen, halo,        cyano, methoxy and methyl);    -   R₁₆ and R₁₈ are selected from hydrogen, halo, cyano, C₁₋₄ alkyl,        C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄haloalkoxy, C₃₋₄cycloalkyl, a        3- to 4-membered heterocyclyl and C₃₋₄-cycloalkoxy;    -   R₁₇ is selected from hydrogen, halo, cyano, C₁₋₄ alkyl, C₁₋₄        haloalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, C₂₋₄ alkenyl, C₂₋₄        alkynyl, phenyl, a 5- or 6-membered or heteroaryl,        C₃₋₆cycloalkyl, —O—C₃₋₆cycloalkyl, heterocyclyl, —O-heterocyclyl        (carbon-linked), —(OCH₂CH₂)_(m)—OCH₃ wherein m is an integer        from 1 to 6, NR_(q)R_(r), wherein R_(q) and R_(r) are each        independently hydrogen, C₁₋₅ alkyl, C₃₋₆cycloalkyl, a 3- to        6-membered carbon-linked heterocyclyl, or R_(q) and R_(r) are        linked together such that, together with the nitrogen atom to        which they are attached, they form a 3- to 6-membered        heterocyclic ring; wherein any C₁₋₅alkyl, C₁₋₄ alkoxy,        C₂₋₄alkenyl, C₂₋₄alkynyl, phenyl, 5- or 6-membered or        heteroaryl, C₃₋₆cycloalkyl, —O—C₃₋₆cycloalkyl, heterocyclyl or        —O— heterocyclyl (carbon-linked) is optionally further        substituted by one or more substituents selected from C₁₋₂alkyl,        cyano, C₁₋₂haloalkyl, hydroxy, C₁₋₂alkoxy, halo, C₁₋₂haloalkoxy,        NR_(1ea)R_(1fa) or —S(O)₀₋₂R_(1ea)R_(1fa), wherein R_(1ea) and        R_(1fa) are H or C₁₋₂alkyl;    -   R₁₉ and R₂₀ are selected from hydrogen, halo, cyano and C₁₋₄        alkyl;    -   R₂₂ and R₂₃ are selected from hydrogen, halo, cyano, C₁₋₄ alkyl,        C₁₋₄ haloalkyl, C₁₋₄alkoxy, C₁₋₄ haloalkoxy (e.g. hydrogen,        halo, cyano and methyl;    -   R₂₈ and R₂₉ are selected from hydrogen, halo, methoxy and        methyl;    -   R₂₁, R₂₄ and R₃₀ are hydrogen or C₁₋₄alkyl.

Particular compounds of the invention include, for example, compounds offormula (I), or pharmaceutically acceptable salts thereof, wherein,unless otherwise stated, each of X, Y, Z, R_(1a), R_(1b), R_(1c),R_(1d), R_(1e), R_(1f), R_(2a), R_(2b), R_(2c), R_(2d), Q₁, Q_(2a),Q_(2b), Q_(2c), Q_(2d), Q₃, Q₄, R_(3a1), R_(3a2), R_(3b1), R_(3b2),R_(3c1), R_(3c2), R_(3d1), R_(3d2), R_(3e1), R_(3e2), R_(3f1), R_(3f2),R_(3g1), R_(3g2), R_(3h1), R_(3h2), R_(3i1), R_(3i2), R_(3j1), R_(3j2),R_(3k1), R_(3k2), R_(3l1), R_(3l2), R_(3m1), R_(3m2), R_(3n1), R_(3n2),R_(3o1), R_(3o2), R_(3p1), R_(3p2), n, R₄, R₅, R_(X5a), R_(X5b), R₆, R₇,R₈, R₉, R₁₀, R₁₁, R_(11N), R₁₂, R₁₃, R₁₆, R₁₇, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂,R₂₃, R₂₄, R₂₈, R₂₉, R₃₀, R_(Z1), R_(Z1a), R_(Z1b), R_(Z1c), R_(Z1d),R_(Z2), R_(Z2a), R_(Z3a), R_(Zi1b), R_(Zi2e), R_(Z9), R_(Z10), R_(Z11),R_(Z12), R_(Z13), R_(Z14), R_(Z15), R_(Z16), A₁, A₂, A₅, A₆, A₇, A₈, A₉,A₁₁, and any associated substituent groups has any of the meaningsdefined hereinbefore or in any one of paragraphs (1) to (193)hereinafter:—

-   -   (1) Q₁ is selected from O, NH or N—C₁₋₄alkyl.    -   (2) Q₁ is selected from NH or N—C₁₋₄alkyl.    -   (3) Q₁ is selected from NH or N—CH₃.    -   (4) Q₁ is NH.    -   (5) Q₂, is CR_(2a);    -   (6) Q_(2b) is CR_(2b);    -   (7) Q_(2c) is CR_(2c);    -   (8) Q_(2d) is CR_(2d);    -   (9) Q₃ is CR_(1b);    -   (10) Q₄ is CR_(1x);    -   (11) X is selected from:

-   -   -   wherein Q₁, R_(1a), R_(1b), R_(1x), R_(2a), R_(2b), R_(2c),            R_(2d) are as defined herein.

    -   (12) X is selected from:

-   -   -   wherein Q₁, R_(1a), R_(1b), R_(2a), R_(2b), R_(2c) and            R_(2d) are as defined herein.

    -   (13) X is selected from:

-   -   -   wherein Q₁, R_(1a), R_(1b), R_(2a), R_(2b) and R_(2d) are as            defined herein.

    -   (14) X is selected from:

-   -   -   wherein Q₁, R_(1a), R_(1b), R_(2a), R_(2b) and R_(2d) are as            defined herein.

    -   (15) X is:

-   -   -   wherein Q₁, R_(1a), R_(1b), R_(2a), R_(2b) and R_(2d) are as            defined herein.

    -   (16)

-   -   -   wherein Q₁, R_(1a), R_(1b), R_(2a) and R_(2d) are as defined            herein.

    -   (17) R_(1b), R_(2a), R_(2b), R₂, and R_(2d) are each        independently selected from hydrogen, C₁₋₂alkyl or halo.

    -   (18) X is selected from:

-   -   -   wherein Q₁ and R_(1a) are as defined herein.

    -   (19) X is selected from:

-   -   -   wherein Q₁ and R_(1a) are as defined herein.

    -   (20) X is selected from:

-   -   -   wherein Q₁ and R_(1a) are as defined herein.

    -   (21) X is selected from:

-   -   -   wherein R_(1a) is as defined herein.

    -   (22) X is selected from:

-   -   -   wherein R_(1a) is as defined herein.

    -   (23) R_(1a) is selected from:        -   (i) C₁₋₄alkyl optionally subsisted by halo, cyano, hydroxy,            C₃₋₆cycloalkyl, C₁₋₄-alkoxy, C₁₋₄haloalkoxy, aryl or            heteroaryl; or        -   (ii) a group of the formula:

—(CR_(1c)R_(1d))_(p)—NR_(1e)R_(1f);

-   -   -   wherein            -   p is an integer selected from 0, 1, 2 or 3            -   R_(1c) and R_(1d) are independently selected from:                -   (i) hydrogen (including deuterium),                -   (ii) C₁₋₆alkyl which is optionally substituted by                    one more substituents selected from cyano, hydroxy,                    C₁₋₄alkoxy, halo, C₁₋₄haloalkoxy, C₃₋₆cycloalkyl,                    —O—C₃₋₆cycloalkyl, NR_(1ca)R_(1da) or                    —S(O)₀₋₂R_(1ca)R_(1da), wherein R_(1ca) and R_(1da)                    are H or C₁₋₂alkyl; and wherein C₃₋₆cycloalkyl and                    —O—C₃₋₆cycloalkyl are optionally further substituted                    with halo, cyano or hydroxy;                -   (iii) C₃₋₄cycloalkyl or 3 to 5 membered                    heterocyclyl, each of which is optionally                    substituted by C₁₋₄alkyl, C₁₋₄haloalkyl, cyano,                    hydroxy, C₁₋₂alkoxy, halo, C₁₋₂haloalkoxy,                    NR_(1ca)R_(1da) or —S(O)₀₋₂R_(1ca)R_(1da), wherein                    R_(1ca) and R_(1da) are H or C₁₋₂alkyl; and;                -   (iv) or R_(1c) and R_(1d) are linked together such                    that, together with the carbon atom to which they                    are attached, they form a 3- to 6-membered                    cycloalkyl or heterocyclic ring, or a spirocyclic                    ring system, each of which is optionally substituted                    by one or more substituents selected from C₁₋₂alkyl,                    C₁₋₂haloalkyl, cyano, hydroxy, C₁₋₂alkoxy, halo,                    C₁₋₂haloalkoxy, NR_(1ca)R_(1da) or                    —S(O)₀₋₂R_(1ca)R_(1da), wherein R_(1ca) and R_(1da)                    are H or C₁₋₂alkyl;        -   R_(1e) and R_(1f) are each independently selected from:            -   (i) hydrogen (including deuterium);            -   (ii) C₁₋₆alkyl which is optionally substituted by one                more substituents selected from cyano, oxo, hydroxy,                C₁₋₂alkoxy, halo, C₁₋₂haloalkoxy, NR_(1ea)R_(1fa) or                —S(O)₀₋₂R_(1ea)R_(1fa), wherein R_(1ea) and R_(1fa) are                H or C₁₋₂alkyl;            -   (iii) a group with the formula:

—(CR_(1g)R_(1h))_(q)-T₁

-   -   -   -   -   wherein:                -   q is 0, 1, 2, 3, 4, 5 or 6;                -   R_(1g) and R_(1h) are independently selected from:                -   a) hydrogen;                -   b) C₁₋₆alkyl which is optionally substituted by one                    more substituents selected from cyano, oxo, hydroxy,                    C₁₋₄alkoxy, halo, C₁₋₄haloalkoxy, —O—C₃₋₆cycloalkyl,                    NR_(1ga)R_(1ha) or —S(O)₀₋₂R_(1ga)R_(1ha), wherein                    R_(1ga) and R_(1ha) are H or C₁₋₂alkyl; and wherein                    —O—C₃₋₆cycloalkyl is optionally substituted with                    halo, cyano or hydroxy;                -   c) an aryl-C₁₋₆alkyl, heteroarylC₁₋₆alkyl,                    C₃₋₆cycloalkyl or C₃₋₆cycloalkylC₁₋₆alkyl group,                    each of which is optionally substituted by one or                    more substituents selected from C₁₋₂alkyl, cyano,                    C₁₋₂haloalkyl, hydroxy, C₁₋₂alkoxy, halo,                    C₁₋₂haloalkoxy, NR_(1ga)R_(1ha) or                    —S(O)₀₋₂R_(1ga)R_(1ha), wherein R_(1ga) and R_(1ha)                    are H or C₁₋₂alkyl; or                -   d) or R_(1g) and R_(1h) are optionally linked                    together such that, together with the carbon atom to                    which they are attached, they form a 3- to                    6-membered cycloalkyl or heterocyclic ring which is                    optionally substituted by one or more substituents                    selected from C₁₋₂alkyl, cyano, C₁₋₂haloalkyl,                    hydroxy, C₁₋₂alkoxy, halo, C₁₋₂haloalkoxy,                    NR_(1ga)R_(1ha) or —S(O)₀₋₂R_(1ga)R_(1ha), wherein                    R_(1ga) and R_(1ha) are H or C₁₋₂alkyl; and T₁ is                    selected from hydrogen, cyano, hydroxy,                    NR_(1t)R_(2t) or —S(O)₀₋₂R_(1t)R_(2t) (wherein                    R_(1t) and R_(2t) are H or C₁₋₄alkyl),                    C₃₋₈cycloalkyl, C₂₋₃alkenyl, C₂₋₃alkynyl, aryl,                    heterocyclyl, heteroaryl, a spirocyclic carbocyclic                    or heterocyclic ring system, a bridged                    C₃₋₈cycloalkyl, a bridged bicyclic C₅₋₁₂cycloalkyl,                    or a bridged heterocyclic ring system, each of which                    is optionally substituted by one or more                    substituents selected from C₁₋₂alkyl, C₁₋₂haloalkyl,                    cyano, hydroxy, C₁₋₂alkoxy, halo, C₁₋₂haloalkoxy,                    NR_(3t)R_(4t) or —S(O)₀₋₂R_(3t)R_(4t), wherein                    R_(3t) and R_(4t) are H or C₁₋₂alkyl;

            -   or R_(1e) and R_(1f) are linked such that, together with                the nitrogen atom to which they are attached, they form                a mono- or bicyclic-heterocyclic ring, which is                optionally substituted by one or more substituents                selected from C₁₋₄alkyl, C₁₋₄ haloalkyl, cyano, hydroxy,                C₁₋₄alkoxy, halo, C₁₋₄haloalkoxy, NR_(1i)R_(1j) or                —S(O)₀₋₂R_(1i)R_(1j), wherein R_(1i) and R_(1j) are H or                C₁₋₄alkyl, and/or the mono- or bicyclic hetereocyclic                ring formed by R_(1e) and R_(1f) is optionally                spiro-fused to a C₃₋₆cycloalkyl or a heterocyclic ring,                which in turn is optionally substituted by one or more                substituents selected from C₁₋₄alkyl, C₁₋₄haloalkyl,                cyano, hydroxy, C₁₋₄ alkoxy, halo, C₁₋₄haloalkoxy,                NR_(1i)R_(1j) or —S(O)₀₋₂R_(1i)R_(1j), wherein R_(1i)                and R_(1j) are H or C₁₋₄alkyl;

    -   (24) R_(1a) is selected from:        -   (i) C₁₋₄alkyl optionally subsisted by halo, cyano, hydroxy,            C₃₋₆cycloalkyl, a 3 to 6 membered heterocyclyl, C₁₋₄alkoxy,            C₁₋₄haloalkoxy, aryl or heteroaryl; or        -   (ii) a group of the formula:

—(CR_(1c)R_(1d))_(p)—NR_(1e)R_(1f);

-   -   -   wherein            -   p is an integer selected from 1 or 2;            -   R_(1c) and R_(1d) are independently selected from:                -   (i) hydrogen (including deuterium),                -   (ii) C₁₋₃alkyl which is optionally substituted by                    one more substituents selected from cyano, oxo,                    hydroxy, C₁₋₄alkoxy, halo, C₁₋₄haloalkoxy,                    —O—C₃₋₆cycloalkyl, NR_(1ca)R_(1da) or                    —S(O)₀₋₂R_(1ca)R_(1da), wherein R_(1ca) and R_(1da)                    are H or C₁₋₂alkyl; and wherein C₃₋₆cycloalkyl and                    —O—C₃₋₆cycloalkyl are optionally substituted with                    halo, cyano or hydroxy;                -   (iii) C₃₋₄cycloalkyl or 3 to 5 membered                    heterocyclyl, each of which is optionally                    substituted by C₁₋₄alkyl, C₁₋₄haloalkyl, cyano,                    hydroxy, C₁₋₂ alkoxy, halo, C₁₋₂haloalkoxy,                    NR_(1ca)R_(1da) or —S(O)₀₋₂R_(1ca)R_(1da), wherein                    R_(1ca) and R_(1da) are H or C₁₋₂alkyl; and;                -   (iv) or R_(1c) and R_(1d) are linked together such                    that, together with the carbon atom to which they                    are attached, they form a 3- to 5-membered                    cycloalkyl or heterocyclic ring, or a spirocyclic                    ring system, each of which is optionally substituted                    by one or more substituents selected from C₁₋₂alkyl,                    C₁₋₂haloalkyl, cyano, hydroxy, C₁₋₂alkoxy, halo,                    C₁₋₂-haloalkoxy, NR_(1ca)R_(1da) or                    —S(O)₀₋₂R_(1ca)R_(1da), wherein R_(1ca) and R_(1da)                    are H or C₁₋₂alkyl;        -   R_(1e) and R_(1f) are each independently selected from:            -   (i) hydrogen (including deuterium);            -   (ii) C₁₋₆alkyl which is optionally substituted by one                more substituents selected from cyano, oxo, hydroxy,                C₁₋₂alkoxy, halo, C₁₋₂haloalkoxy, NR_(1ea)R_(1fa) or                —S(O)₀₋₂R_(1ea)R_(1fa), wherein R_(1ea) and R_(1fa) are                H or C₁₋₂alkyl;            -   (iii) a group with the formula:

—(CR_(1g)R_(1h))_(q)-T₁

-   -   -   -   -   wherein:                -   q is 0, 1, 2 or 3;

            -   R_(1g) and R_(1h) are independently selected from:                -   a) hydrogen (including deuterium); or                -   b) C₁₋₃alkyl which is optionally substituted by one                    more substituents selected from cyano, oxo, hydroxy,                    C₁₋₃alkoxy, halo, C₁₋₄haloalkoxy, —O—C₃₋₄cycloalkyl,                    wherein —O—C₃₋₄cycloalkyl is optionally substituted                    with halo, cyano or hydroxy, NR_(1ca)R_(1da) or                    —S(O)₀₋₂R_(1ca)R_(1da), wherein R_(1ca) and R_(1da)                    are H or C₁₋₂alkylNR_(1ga)R_(1ha) or                    —S(O)₀₋₂R_(1ga)R_(1ha), wherein R_(1ga) and R_(1ha)                    are H or C₁₋₂alkyl;                -   c) or R_(1g) and R_(1h) are optionally linked                    together such that, together with the carbon atom to                    which they are attached, they form a 3- to                    6-membered cycloalkyl or heterocyclic ring which is                    optionally substituted by one or more substituents                    selected from C₁₋₂alkyl, C₁₋₂-haloalkyl, cyano,                    hydroxy, C₁₋₂alkoxy, halo, C₁₋₂ haloalkoxy,                    NR_(1ga)R_(1ha) or —S(O)₀₋₂R_(1ga)R_(1ha), wherein                    Riga and R_(1a), are H or C₁₋₂alkyl;

            -   and T₁ is selected from hydrogen, halo, C₁₋₄alkyl,                C₁₋₄haloalkyl, cyano, hydroxy, NR_(1t)R_(2t) or                —S(O)₀₋₂R_(1t)R_(2t) (wherein R_(1t) and R_(2t) are H or                C₁₋₄alkyl), C₃₋₈cycloalkyl, C₂₋₃alkenyl, C₂₋₃alkynyl,                aryl, heterocyclyl, a mono- or bicyclic heteroaryl, a                spirocyclic carbocyclic or heterocyclic ring system, a                bridged C₃₋₈cycloalkyl, a bridged bicyclic                C₅₋₁₂cycloalkyl, or a bridged heterocyclic ring system,                each of which is optionally substituted by one or more                substituents selected from C₁₋₂alkyl, C₁₋₂haloalkyl,                cyano, hydroxy, C₁₋₂alkoxy, halo, C₁₋₂haloalkoxy,                C₃₋₆cycloalkyl, NR_(3t)R_(4t) or —S(O)₀₋₂R_(3t)R_(4t),                wherein R_(3t) and R_(4t) are H or C₁₋₂alkyl;

        -   (iv) or R_(1e) and R_(1f) are linked such that, together            with the nitrogen atom to which they are attached, they form            a mono- or bicyclic-heterocyclic ring, which is optionally            substituted by one or more substituents selected from            C₁₋₄alkyl, C₁₋₄haloalkyl, C₃₋₆cycloalkyl, cyano, hydroxy,            C₁₋₄alkoxy, halo, C₁₋₄haloalkoxy, NR_(1i)R_(1j) or            —S(O)₀₋₂R_(1i)R_(1j), wherein R_(1i) and R_(1j) are H or            C₁₋₄alkyl, and/or the mono- or bicyclic hetereocyclic ring            formed by R_(1e) and R_(1f) is optionally spiro-fused to a            C₃₋₆cycloalkyl or a heterocyclic ring, which in turn is            optionally substituted by one or more substituents selected            from C₁₋₄alkyl, C₁₋₄haloalkyl, C₃₋₆cycloalkyl, cyano,            hydroxy, C₁₋₄alkoxy, halo, C₁₋₄haloalkoxy, NR_(1i)R_(1j) or            —S(O)₀₋₂R_(1i)R_(1j), wherein R_(1i) and R_(1j) are H or            C₁₋₄alkyl;            -   wherein any wherein any alkyl, alkoxy or C₃₋₆cycloalkyl                is further optionally substituted by one or more                substituents selected from cyano, hydroxy, halo,                NR_(1k)R_(1l) or —S(O)₀₋₂R_(1k)R_(1l), wherein R_(1k)                and R_(1l) are H or C₁₋₄alkyl;

    -   (25) R_(1a) is a group of the formula:

—(CR_(1c)R_(1d))_(p)—NR_(1e)R_(1f);

-   -   -   wherein            -   p is an integer selected from 1 or 2;        -   R_(1c) and R_(1d) are independently selected from:            -   (i) hydrogen (including deuterium); or            -   (ii) C₁₋₃alkyl which is optionally substituted by one                more substituents selected from cyano, oxo, hydroxy,                C₁₋₃alkoxy, halo, C₁₋₃haloalkoxy, —O—C₃₋₄cycloalkyl, or                NH₂; wherein —O—C₃₋₈cycloalkyl is optionally substituted                with halo, cyano or hydroxy,            -   (iii) C₃₋₄cycloalkyl which is optionally substituted by                C₁₋₄alkyl, C₁₋₄haloalkyl, cyano, hydroxy, C₁₋₂alkoxy,                halo, C₁₋₂haloalkoxy or NR_(1ca)R_(1d)a; and; (iv) or                R_(1c) and R_(1d) are linked together such that,                together with the carbon atom to which they are                attached, they form a 3- to 5-membered cycloalkyl or                heterocyclic ring, or a spirocyclic ring system, each of                which is optionally substituted by one or more                substituents selected from C₁₋₂alkyl, C₁₋₂haloalkyl,                cyano, hydroxy, C₁₋₂alkoxy, halo, C₁₋₂-haloalkoxy,                NR_(1ca)R_(1da) or —S(O)₀₋₂R_(1ca)R_(1da), wherein                R_(1ca) and R_(1da) are H or C₁₋₂alkyl;        -   R_(1e) and R_(1f) are each independently selected from:            -   (i) hydrogen (including deuterium);            -   (ii) C₁₋₆alkyl which is optionally substituted by one                more substituents selected from cyano, oxo, hydroxy,                C₁₋₂alkoxy, halo, C₁₋₂haloalkoxy, NH₂;            -   (iii) a group with the formula:

—(CR_(1g)R_(1h))_(q)-T₁

-   -   -   -   -   wherein:                -   q is 0, 1, 2 or 3;

            -   R_(1g) and R_(1h) are independently selected from:                -   a) hydrogen (including deuterium); or                -   b) C₁₋₆alkyl which is optionally substituted by one                    more substituents selected from cyano, oxo, hydroxy,                    C₁₋₄alkoxy, halo, C₁₋₄haloalkoxy, —O—C₃₋₆cycloalkyl,                    NR_(1ca)R_(1da) or —S(O)₀₋₂R_(1ca)R_(1da), wherein                    R_(1ca) and R_(1da) are H or                    C₁-2alkylNR_(1ga)R_(1ha) or —S(O)₀₋₂R_(1ga)R_(1ha),                    wherein R_(1ga) and R_(1ha) are H or C₁₋₂alkyl; and                    wherein —O—C₃₋₆cycloalkyl is optionally substituted                    with halo, cyano or hydroxy,                -   c) or R_(1g) and R_(1h) are optionally linked                    together such that, together with the carbon atom to                    which they are attached, they form a 3- to                    6-membered cycloalkyl or heterocyclic ring which is                    optionally substituted by one or more substituents                    selected from C₁₋₂alkyl, C₁₋₂-haloalkyl, cyano,                    hydroxy, C₁₋₂alkoxy, halo, C₁₋₂haloalkoxy,                    NR_(1ga)R_(1ha) or —S(O)₀₋₂R_(1ga)R_(1ha), wherein                    R_(1ga) and R_(1ha) are H or C₁₋₂alkyl;

            -   and T₁ is selected from hydrogen, halo, C₁₋₄alkyl,                C₁₋₄haloalkyl, cyano, hydroxy, NR_(1t)R_(2t) or                —S(O)₀₋₂R_(1t)R_(2t) (wherein R_(1t) and R_(2t) are H or                C₁₋₄alkyl), C₃₋₈cycloalkyl, C₂₋₃alkenyl, C₂₋₃alkynyl,                aryl, heterocyclyl, a mono- or bicyclic heteroaryl, a                spirocyclic carbocyclic or heterocyclic ring system, a                bridged C₃₋₈cycloalkyl, a bridged bicyclic                C₅₋₁₂cycloalkyl, or a bridged heterocyclic ring system,                each of which is optionally substituted by one or more                substituents selected from C₁₋₂alkyl, C₁₋₂haloalkyl,                cyano, hydroxy, C₁₋₂alkoxy, halo, C₁₋₂haloalkoxy,                C₃₋₆cycloalkyl, NR_(3t)R_(4t) or —S(O)₀₋₂R_(3t)R_(4t),                wherein R_(3t) and R_(4t) are H or C₁₋₂alkyl;

        -   (iv) or R_(1e) and R_(1f) are linked such that, together            with the nitrogen atom to which they are attached, they form            a mono- or bicyclic-heterocyclic ring, which is optionally            substituted by one or more substituents selected from            C₁₋₄alkyl, C₁₋₄haloalkyl, C₃₋₆cycloalkyl, cyano, hydroxy,            C₁₋₄alkoxy, halo, C₁₋₄haloalkoxy, NR_(1i)R_(1j) or            —S(O)₀₋₂R_(1i)R_(1j), wherein R_(1i) and R_(1j) are H or            C₁₋₄alkyl, and/or the mono- or bicyclic hetereocyclic ring            formed by R_(1e) and R_(1f) is optionally spiro-fused to a            C₃₋₆cycloalkyl or a heterocyclic ring, which in turn is            optionally substituted by one or more substituents selected            from C₁₋₄alkyl, C₁₋₄haloalkyl, C₃₋₆cycloalkyl, cyano,            hydroxy, C₁₋₄alkoxy, halo, C₁₋₄haloalkoxy, NR_(1i)R_(1j) or            —S(O)₀₋₂R_(1i)R_(1j), wherein R_(1i) and R_(1j) are H or            C₁₋₄alkyl;

        -   wherein any wherein any alkyl, alkoxy or C₃₋₆cycloalkyl is            further optionally substituted by one or more substituents            selected from cyano, hydroxy, halo, NR_(1k)R_(1l) or            —S(O)₀₋₂R_(1k)R_(1l), wherein R_(1k) and R_(1l) are H or            C₁₋₄alkyl.

    -   (26) R_(1a) is a group of the formula:

—(CR_(1c)R_(1d))_(p)—NR_(1e)R_(1f);

wherein

-   -   p is an integer selected from 1 or 2;        R_(1c) and R_(1d) are independently selected from:    -   (i) hydrogen (including deuterium),    -   (ii) C₁₋₃alkyl which is optionally substituted by one more        substituents selected from cyano, oxo, hydroxy, C₁₋₃alkoxy,        halo, C₁₋₄₃haloalkoxy, —O—C₃₋₄cycloalkyl, or NH₂; wherein        —O—C₃₋₆cycloalkyl is optionally substituted with halo, cyano or        hydroxy,    -   (iii) or R_(1c) and R_(1d) are linked together such that,        together with the carbon atom to which they are attached, they        form a 3- to 5-membered cycloalkyl or heterocyclic ring, or a        spirocyclic ring system, each of which is optionally substituted        by one or more substituents selected from C₁₋₂alkyl,        C₁₋₂haloalkyl, cyano, hydroxy, C₁₋₂alkoxy, halo, C₁₋₂haloalkoxy,        NR_(1ca)R_(1da) or —S(O)₀₋₂R_(1ca)R_(1da), wherein R_(1ca) and        R_(1da) are H or C₁₋₂alkyl;        R_(1e) is selected from:    -   (i) hydrogen (including deuterium);    -   (ii) C₁₋₃alkyl which is optionally substituted by one more        substituents selected from cyano, oxo, hydroxy, C₁₋₂alkoxy,        halo, C₁₋₂haloalkoxy and NH₂;        and R_(1f) is selected from:    -   (i) C₁₋₆alkyl which is optionally substituted by one more        substituents selected from cyano, oxo, hydroxy, C₁₋₂alkoxy,        halo, C₁₋₂haloalkoxy and NH₂;    -   (ii) a group with the formula:

—(CR_(1g)R_(1h))_(q)-T₁

-   -   -   wherein:        -   q is 1, 2 or 3;

    -   R_(1g) and R_(1h) are independently selected from:        -   a) hydrogen (including deuterium); or        -   b) C₁₋₆alkyl which is optionally substituted by one more            substituents selected from cyano, oxo, hydroxy, C₁₋₄alkoxy,            halo, C₁₋₄haloalkoxy, —O—C₃₋₆cycloalkyl, NR_(1ca)R_(1da) or            —S(O)₀₋₂R_(1ca)R_(1da), wherein R_(1ca) and R_(1da) are H or            C₁₋₂alkylNR_(1ga)R_(1ha) or —S(O)₀₋₂R_(1ga)R_(1ha), wherein            R_(1ga) and R_(1ha) are H or C₁₋₂alkyl; and wherein            —O—C₃₋₆cycloalkyl is optionally substituted with halo, cyano            or hydroxy;        -   c) or R_(1g) and R_(1h) are optionally linked together such            that, together with the carbon atom to which they are            attached, they form a 3- to 4-membered cycloalkyl or            heterocyclic ring which is optionally substituted by one or            more substituents selected from C₁₋₂alkyl, C₁₋₂-haloalkyl,            cyano, hydroxy, C₁₋₂alkoxy, halo, C₁₋₂-haloalkoxy,            NR_(1ga)R_(1ha) or —S(O)₀₋₂R_(1ga)R_(1ha), wherein R_(1ga)            and R_(1ha) are H or C₁₋₂alkyl;

    -   and T₁ is selected from hydrogen, halo, C₁₋₄alkyl,        C₁₋₄haloalkyl, cyano, hydroxy, NR_(1t)R_(2t) or        —S(O)₀₋₂R_(1t)R_(2t) (wherein R_(1t) and R_(2t) are H or        C₁₋₄alkyl), C₃₋₈cycloalkyl, C₂₋₃alkenyl, C₂₋₃alkynyl, aryl,        heterocyclyl, a mono- or bicyclic heteroaryl, a spirocyclic        carbocyclic or heterocyclic ring system, a bridged        C₃₋₈cycloalkyl, a bridged bicyclic C₅₋₁₂cycloalkyl, or a bridged        heterocyclic ring system, each of which is optionally        substituted by one or more substituents selected from C₁₋₂alkyl,        C₁₋₂haloalkyl, cyano, hydroxy, C₁₋₂alkoxy, halo, C₁₋₂haloalkoxy,        C₃₋₆cycloalkyl, NR_(3t)R_(4t) or —S(O)₀₋₂R_(3t)R_(4t), wherein        R_(3t) and R_(4t) are H or C₁₋₂alkyl;

    -   or R_(1e) and R_(1f) are linked such that, together with the        nitrogen atom to which they are attached, they form a mono- or        bicyclic-heterocyclic ring, which is optionally substituted by        one or more substituents selected from C₁₋₄alkyl, C₁₋₄haloalkyl,        C₃₋₆cycloalkyl, cyano, hydroxy, C₁₋₄alkoxy, halo,        C₁₋₄haloalkoxy, NR_(1i)R_(1j) or —S(O)₀₋₂R_(1i)R_(1j), wherein        R_(1i) and R_(1j) are H or C₁₋₄alkyl, and/or the mono- or        bicyclic hetereocyclic ring formed by R_(1e) and R_(1f) is        optionally spiro-fused to a C₃₋₆cycloalkyl or a heterocyclic        ring; which in turn is optionally substituted by one or more        substituents selected from C₁₋₄alkyl, C₁₋₄haloalkyl,        C₃₋₆cycloalkyl, cyano, hydroxy, C₁₋₄alkoxy, halo,        C₁₋₄haloalkoxy, NR_(1i)R_(1j) or —S(O)₀₋₂R_(1i)R_(1j), wherein        R_(1i) and R_(1j) are H or C₁₋₄alkyl;

    -   wherein any wherein any alkyl, alkoxy or C₃₋₆cycloalkyl is        further optionally substituted by one or more substituents        selected from cyano, hydroxy, halo, NR_(1k)R_(1l) or        —S(O)₀₋₂R_(1k)R_(1l), wherein R_(1k) and R_(1l) are H or        C₁₋₄alkyl.

    -   (27) R_(1a) is a group of the formula:

—(CR_(1c)R_(1d))_(p)—NR_(1e)R_(1f)

wherein

-   -   p is an integer selected from 1 or 2;        R_(1c) and R_(1d) are independently selected from:    -   (i) hydrogen (including deuterium),    -   (ii) C₁₋₃alkyl which is optionally substituted by one more        substituents selected from cyano, oxo, hydroxy, C₁₋₃alkoxy,        halo, C₁₋₃haloalkoxy, —O—C₃₋₄cycloalkyl, or NH₂; wherein        —O—C₃₋₆cycloalkyl is optionally substituted with halo, cyano or        hydroxy,    -   (iii) or R_(1c) and R_(1d) are linked together such that,        together with the carbon atom to which they are attached, they        form a 3- to 5-membered cycloalkyl or heterocyclic ring, or a        spirocyclic ring system, each of which is optionally substituted        by one or more substituents selected from C₁₋₂alkyl,        C₁₋₂haloalkyl, cyano, hydroxy, C₁₋₂alkoxy, halo or        C₁₋₂haloalkoxy;        R_(1e) is selected from:    -   (i) hydrogen (including deuterium);    -   (ii) C₁₋₃alkyl which is optionally substituted by one more        substituents selected from cyano, oxo, hydroxy, C₁₋₂alkoxy,        halo, C₁₋₂haloalkoxy and NH₂;        R_(1f) is a group with the formula:

—(CR_(1g)R_(1h))_(q)-T₁

-   -   wherein:    -   q is 1, 2 or 3;

R_(1g) and R_(1h) are independently selected from:

-   -   a) hydrogen (including deuterium); or    -   b) C₁₋₃alkyl which is optionally substituted by one more        substituents selected from cyano, oxo, hydroxy, C₁₋₄ alkoxy,        halo, C₁₋₄haloalkoxy, —O—C₃₋₆cycloalkyl, wherein        —O—C₃₋₆cycloalkyl is optionally substituted with halo, cyano or        hydroxy;    -   c) or R_(1g) and R_(1h) are optionally linked together such        that, together with the carbon atom to which they are attached,        they form a 3- to 4-membered cycloalkyl or heterocyclic ring        which is optionally substituted by one or more substituents        selected from C₁₋₂alkyl, C₁₋₂-haloalkyl, cyano, hydroxy,        C₁₋₂alkoxy, halo or C₁₋₂-haloalkoxy;    -   and T₁ is selected from halo, C₁₋₄alkyl, C₁₋₄haloalkyl, cyano,        hydroxy, NR_(1t)R_(2t) or —S(O)₀₋₂R_(1t)R_(2t) (wherein R_(1t)        and R_(2t) are H or C₁₋₄alkyl), C₃₋₈ cycloalkyl, C₂₋₃alkenyl,        C₂₋₃alkynyl, aryl, heterocyclyl, a mono- or bicyclic heteroaryl,        a spirocyclic carbocyclic or heterocyclic ring system, a bridged        C₃₋₈cycloalkyl, a bridged bicyclic C₅₋₁₂cycloalkyl, or a bridged        heterocyclic ring system, each of which is optionally        substituted by one or more substituents selected from C₁₋₂alkyl,        C₁₋₂-haloalkyl, cyano, hydroxy, C₁₋₂alkoxy, halo,        C₁₋₂haloalkoxy, C₃₋₆cycloalkyl, NR_(3t)R_(4t) or        —S(O)₀₋₂R_(3t)R_(4t), wherein R_(3t) and R_(4t) are H or        C₁₋₂alkyl;    -   or R_(1e) and R_(1f) are linked such that, together with the        nitrogen atom to which they are attached, they form a mono- or        bicyclic-heterocyclic ring, which is optionally substituted by        one or more substituents selected from C₁₋₄alkyl, C₁₋₄haloalkyl,        C₃₋₆cycloalkyl, cyano, hydroxy, C₁₋₄alkoxy, halo,        C₁₋₄haloalkoxy, NR_(1i)R_(1j) or —S(O)₀₋₂R_(1i)R_(1j), wherein        R_(1i) and R_(1j) are H or C₁₋₄alkyl, and/or the mono- or        bicyclic hetereocyclic ring formed by R_(1e) and R_(1f) is        optionally spiro-fused to a C₃₋₆cycloalkyl or a heterocyclic        ring, which in turn is optionally substituted by one or more        substituents selected from C₁₋₄alkyl, C₁₋₄haloalkyl,        C₃₋₆cycloalkyl, cyano, hydroxy, C₁₋₄alkoxy, halo,        C₁₋₄haloalkoxy, NR_(1i)R_(1j) or —S(O)₀₋₂R_(1i)R_(1j), wherein        R_(1i) and R_(1j) are H or C₁₋₄alkyl;        -   wherein any wherein any alkyl, alkoxy or C₃₋₆cycloalkyl is            further optionally substituted by one or more substituents            selected from cyano, hydroxy, halo, NR_(1k)R_(1l) or            —S(O)₀₋₂R_(1k)R_(1l), wherein R_(1k) and R_(1l) are H or            C₁₋₄alkyl.    -   (28) R_(1a) is a group of the formula:

—(CR_(1c)R_(1a))_(p)—NR_(1e)R_(1f);

wherein

-   -   p is an integer selected from 1 or 2;        R_(1c) and R_(1d) are independently selected from:    -   (i) hydrogen (including deuterium),    -   (ii) C₁₋₃alkyl which is optionally substituted by one more        substituents selected from cyano, oxo, hydroxy, C₁₋₃alkoxy,        halo, C₁₋₃haloalkoxy, —O—C₃₋₄cycloalkyl, or NH₂; wherein        —O—C₃₋₆cycloalkyl is optionally substituted with halo, cyano or        hydroxy,    -   (iii) or R_(1c) and R_(1d) are linked together such that,        together with the carbon atom to which they are attached, they        form a 3- to 5-membered cycloalkyl or heterocyclic ring, or a        spirocyclic ring system, each of which is optionally substituted        by one or more substituents selected from C₁₋₂alkyl,        C₁₋₂haloalkyl, cyano, hydroxy, C₁₋₂alkoxy, halo or        C₁₋₂haloalkoxy;        R_(1e) is selected from:    -   (i) hydrogen (including deuterium);    -   (ii) C₁₋₃alkyl which is optionally substituted by one more        substituents selected from cyano, oxo, hydroxy, C₁₋₂alkoxy,        halo, C₁₋₂haloalkoxy and NH₂;        R_(1f) is a group with the formula:    -   —(CR_(1g)R_(1h))_(q)-T₁    -   wherein:    -   q is 1 or 2;    -   R_(1g) and R_(1h) are independently selected from:        -   a) hydrogen (including deuterium); or        -   b) C₁₋₃alkyl, which is optionally substituted by one more            substituents selected from cyano, oxo, hydroxy, C₁₋₂alkoxy,            halo, C₁₋₂haloalkoxy, —O—C₃cycloalkyl, wherein            —O—C₃cycloalkyl is optionally substituted with halo, cyano            or hydroxy;    -   and T₁ is selected from C₁₋₄alkyl, C₃₋₈cycloalkyl, aryl,        heterocyclyl, heteroaryl, a spirocyclic carbocyclic or        heterocyclic ring system, a bridged C₃₋₈cycloalkyl, a bridged        bicyclic C₅₋₁₂cycloalkyl, or a bridged heterocyclic ring system,        each of which is optionally substituted by one or more        substituents selected from C₁₋₂alkyl, C₁₋₂haloalkyl, cyano,        hydroxy, C₁₋₂alkoxy, halo, C₁₋₂haloalkoxy or C₃₋₆cycloalkyl;    -   or R_(1e) and R_(1f) are linked such that, together with the        nitrogen atom to which they are attached, they form a mono- or        bicyclic-heterocyclic ring, which is optionally substituted by        one or more substituents selected from C₁₋₂alkyl, C₁₋₂haloalkyl,        C₃₋₆cycloalkyl, cyano, hydroxy, C₁₋₂alkoxy, halo,        C₁₋₂haloalkoxy, NR_(1i)R_(1j) or —S(O)₀₋₂R_(1i)R_(1j), wherein        R_(1i) and R_(1j) are H or C₁₋₂alkyl, and/or the mono- or        bicyclic hetereocyclic ring formed by R_(1e) and R_(1f) is        optionally spiro-fused to a C₃₋₆cycloalkyl or a heterocyclic        ring, which in turn is optionally substituted by one or more        substituents selected from C₁₋₂alkyl, C₃₋₆cycloalkyl, cyano,        hydroxy, C₁₋₂alkoxy, halo, C₁₋₂haloalkoxy, NR_(1i)R_(1j) or        —S(O)₀₋₂R_(1i)R_(1j), wherein R_(1i) and R_(1j) are H or        C₁₋₂alkyl;        -   wherein any wherein any alkyl, alkoxy or C₃₋₆cycloalkyl is            further optionally substituted by one or more substituents            selected from cyano, hydroxy, halo, NR_(1k)R_(1l) or            —S(O)₀₋₂R_(1k)R_(1l), wherein R_(1k) and R_(1l) are H or            C₁₋₄alkyl.    -   (29) R_(1a) is a group of the formula:

—(CR_(1c)R_(1d))_(p)—NR_(1e)R_(1f);

wherein

-   -   p is an integer selected from 1 or 2;        R_(1c) and R_(1d) are independently selected from:    -   (i) hydrogen (including deuterium) or    -   (ii) C₁₋₃alkyl which is optionally substituted by one more        substituents selected from cyano, oxo, hydroxy, C₁₋₂alkoxy,        halo, C₁₋₂haloalkoxy, —O—C₃cycloalkyl;        R_(1e) is selected from hydrogen (including deuterium) or        C₁₋₂alkyl; and        R_(1f) is a group with the formula:

—(CR_(1g)R_(1h))_(q)-T₁

-   -   -   wherein:        -   q is 1 or 2;

    -   R_(1g) and R_(1h) are independently selected from:        -   a) hydrogen (including deuterium); or        -   b) C₁₋₂alkyl, which is optionally substituted by one more            substituents selected from cyano, oxo, hydroxy, C₁₋₂ alkoxy,            halo or C₁₋₂haloalkoxy;

    -   and T₁ is selected from C₁₋₄alkyl, C₃₋₆cycloalkyl, aryl,        heterocyclyl, a mono- or bicyclic heteroaryl, a spirocyclic        carbocyclic or heterocyclic ring system, a bridged        C₃₋₆cycloalkyl, a bridged bicyclic C₅₋₁₂cycloalkyl, or a bridged        heterocyclic ring system, each of which is optionally        substituted by one or more substituents selected from C₁₋₂alkyl,        C₁₋₂-haloalkyl, cyano, hydroxy, C₁₋₂alkoxy, halo, C₁₋₂haloalkoxy        or C₃₋₆cycloalkyl;        or R_(1e) and R_(1f) are linked such that, together with the        nitrogen atom to which they are attached, they form a mono- or        bicyclic-heterocyclic ring, which is optionally substituted by        one or more substituents selected from C₁₋₂alkyl, C₁₋₂haloalkyl,        C₃₋₆cycloalkyl, cyano, hydroxy, C₁₋₂alkoxy, halo or        C₁₋₂haloalkoxy, and/or the mono- or bicyclic hetereocyclic ring        formed by R_(1e) and R_(1f) is optionally spiro-fused to a        C₃₋₆cycloalkyl or a heterocyclic ring, which in turn is        optionally substituted by one or more substituents selected from        C₁₋₂alkyl, C₁₋₂-haloalkyl, C₃₋₆cycloalkyl, cyano, hydroxy,        C₁₋₂alkoxy, halo or C₁₋₂haloalkoxy; wherein any wherein any        alkyl, alkoxy or C₃₋₆cycloalkyl is further optionally        substituted by one or more substituents selected from cyano,        hydroxy, halo, NR_(1k)R_(1l) or —S(O)₀₋₂R_(1k)R_(1l), wherein        R_(1k) and R_(1l) are H or C₁₋₄alkyl.

    -   (30) R_(1a) is a group of the formula:

—(CR_(1c)R_(1d))_(p)—NR_(1e)R_(1f);

wherein

-   -   p is an integer selected from 1 or 2;    -   R_(1c) and R_(1d) are independently selected from hydrogen        (including deuterium) or C₁₋₂alkyl;    -   R_(1e) is selected from hydrogen (including deuterium) or        C₁₋₂alkyl; and    -   R_(1f) is a group with the formula:

—(CR_(1g)R_(1h))_(q)-T₁

-   -   -   wherein:        -   q is 1 or 2;

    -   R_(1g) and R_(1h) are independently selected from hydrogen        (including deuterium) or C₁₋₂alkyl;

    -   and T₁ is selected from C₁₋₄alkyl, C₃₋₄cycloalkyl, heterocyclyl,        a mono- or bicyclic heteroaryl, a spirocyclic carbocyclic or        heterocyclic ring system, a bridged C₃-cycloalkyl, a bridged        bicyclic C₅₋₁₂cycloalkyl, or a bridged heterocyclic ring system,        each of which is optionally substituted by one or more        substituents selected from C₁₋₂alkyl, C₁₋₂haloalkyl, cyano,        hydroxy, C₁₋₂alkoxy, halo, C₁₋₂haloalkoxy or C₃₋₆cycloalkyl;

    -   or R_(1e) and R_(1f) are linked such that, together with the        nitrogen atom to which they are attached, they form a mono- or        bicyclic-heterocyclic ring, which is optionally substituted by        one or more substituents selected from C₁₋₂alkyl, C₁₋₂haloalkyl,        C₃₋₆cycloalkyl, cyano, hydroxy, C₁₋₂alkoxy, halo or        C₁₋₂haloalkoxy, and/or the mono- or bicyclic hetereocyclic ring        formed by R_(1e) and R_(1f) is optionally spiro-fused to a        C₃₋₆cycloalkyl or a heterocyclic ring, which in turn is        optionally substituted by one or more substituents selected from        C₁₋₂alkyl, C₁₋₂haloalkyl, C₃₋₆cycloalkyl, cyano, hydroxy,        C₁₋₂alkoxy, halo or C₁₋₂haloalkoxy; wherein any alkyl, alkoxy or        C₃₋₆cycloalkyl is further optionally substituted by one or more        substituents selected from cyano, hydroxy, halo, NR_(1k)R_(1l)        or —S(O)₀₋₂R_(1k)R_(1l), wherein R_(1k) and R_(1l) are H or        C₁₋₄alkyl.

    -   (31) R_(1a) is a group of the formula:

—(CR_(1c)R_(1d))_(p)—NR_(1e)R_(1f);

wherein

-   -   p is 1;    -   R_(1c) and R_(1d) are independently selected from hydrogen        (including deuterium) or C₁₋₂alkyl;    -   R_(1e) is selected from hydrogen (including deuterium) or        C₁₋₂alkyl; and    -   R_(1f) is a group with the formula:

—(CR_(1g)R_(1h))_(q)-T₁

-   -   -   wherein:        -   q is 1 or 2;

    -   R_(1g) and R_(1h) are independently selected from hydrogen        (including deuterium) or C₁₋₂alkyl;

    -   and T₁ is selected from C₃₋₄cycloalkyl, heterocyclyl, a mono- or        bicyclic heteroaryl, a spirocyclic carbocyclic or heterocyclic        ring system, a bridged C₃₋₈cycloalkyl, a bridged bicyclic        C₅₋₁₂cycloalkyl, or a bridged heterocyclic ring system, each of        which is optionally substituted by one or more substituents        selected from C₁₋₂alkyl, C₁₋₂haloalkyl, cyano, hydroxy,        C₁₋₂alkoxy, halo, C₁₋₂-haloalkoxy or C₃₋₆cycloalkyl;

    -   or R_(1e) and R_(1f) are linked such that, together with the        nitrogen atom to which they are attached, they form a mono- or        bicyclic-heterocyclic ring, which is optionally substituted by        one or more substituents selected from C₁₋₂alkyl, C₁₋₂haloalkyl,        C₃₋₆cycloalkyl, cyano, hydroxy, C₁₋₂alkoxy, halo or        C₁₋₂haloalkoxy, and/or the mono- or bicyclic hetereocyclic ring        formed by R_(1e) and R_(1f) is optionally spiro-fused to a        C₃₋₆cycloalkyl or a heterocyclic ring; which in turn is        optionally substituted by one or more substituents selected from        C₁₋₂alkyl, C₁₋₂haloalkyl, C₃₋₆cycloalkyl, cyano, hydroxy,        C₁₋₂alkoxy, halo or C₁₋₂haloalkoxy, wherein any alkyl, alkoxy or        C₃₋₆cycloalkyl is further optionally substituted by one or more        substituents selected from cyano, hydroxy, halo, NR_(1k)R_(1l)        or —S(O)₀₋₂R_(1k)R_(1l), wherein R_(1k) and R_(1l) are H or        C₁₋₄alkyl.

    -   (32) R_(1a) is a group of the formula:

—(CR_(1c)R_(1d))_(p)—NR_(1e)R_(1f);

wherein

-   -   p is 1;    -   R_(1c) and R_(1d) are independently selected from hydrogen        (including deuterium) or C₁₋₂alkyl;    -   R_(1e) is selected from hydrogen (including deuterium) or        C₁₋₂alkyl; and    -   R_(1f) is a group with the formula:

—(CR_(1g)R_(1h))_(q)-T₁

-   -   -   wherein:        -   q is 1;

    -   R_(1g) and R_(1h) are independently selected from hydrogen        (including deuterium) or C₁₋₂alkyl;        -   and T₁ is selected from C₃₋₄cycloalkyl, heterocyclyl, a            spirocyclic carbocyclic or heterocyclic ring system, a            bridged C₃₋₈cycloalkyl, a bridged bicyclic C₅₋₁₂cycloalkyl,            or a bridged heterocyclic ring system, each of which is            optionally substituted by one or more substituents selected            from C₁₋₂alkyl, C₁₋₂haloalkyl, cyano, hydroxy, C₁₋₂alkoxy,            halo, C₁₋₂haloalkoxy or C₃₋₆cycloalkyl,        -   wherein any alkyl or alkoxy is optionally further            substituted by one or more substituents selected from cyano,            hydroxy or halo.

    -   (33) R_(1a) is a group of the formula:

—(CR_(1c)R_(1d))_(p)—NR_(1e)R_(1f);

wherein

-   -   p is 1;    -   R_(1c) and R_(1d) are independently selected from hydrogen        (including deuterium) or C₁₋₂alkyl; and        -   R_(1e) and R_(1f) are linked such that, together with the            nitrogen atom to which they are attached, they form a mono-            or bicyclic-heterocyclic ring, which is optionally            substituted by one or more substituents selected from            C₁₋₂alkyl, C₁₋₂haloalkyl, C₃₋₆cycloalkyl, cyano, hydroxy,            C₁₋₂alkoxy, halo or C₁₋₂haloalkoxy, and/or the mono- or            bicyclic hetereocyclic ring formed by R_(1e) and R_(1f) is            optionally spiro-fused to a C₃₋₆cycloalkyl or a heterocyclic            ring, which in turn is optionally substituted by one or more            substituents selected from C₁₋₂alkyl, C₁₋₂haloalkyl, cyano,            hydroxy, C₁₋₂alkoxy, halo or C₁₋₂haloalkoxy.    -   (34) R_(1a) is

-   -   -   wherein T₁ is as defined herein.

    -   (35) R_(1a) is a group of the formula:

-   -   -   wherein T₁ is selected from C₃₋₄cycloalkyl, heterocyclyl, a            spirocyclic carbocyclic or heterocyclic ring system, a            bridged C₃₋₈cycloalkyl, a bridged bicyclic C₅₋₁₂cycloalkyl,            or a bridged heterocyclic ring system, each of which is            optionally substituted by one or more substituents selected            from C₁₋₂alkyl, C₁₋₂haloalkyl, cyano, hydroxy, C₁₋₂alkoxy,            halo or C₁₋₂haloalkoxy;

    -   (36) R_(1a) is selected from:        methoxy;

-   -   (37) R_(1a) is selected from:

-   -   (38) R_(1a) is selected from

-   -   (39) R_(1a) is selected from:

-   -   (40) R_(1a) is selected from:

-   -   (40a) R_(1a) is selected from:

-   -   (41) R_(1a) is selected from:

-   -   (41a) R_(1a) is:

-   -   (41b) R_(1a) is:

-   -   (41c) R_(1a) is:

-   -   (42) R_(1a) is:

-   -   (43) R_(1b) is selected from hydrogen, halo or C₁₋₂ alkyl.    -   (44) R_(1b) is hydrogen.    -   (45) R_(1x) is selected from hydrogen, halo or C₁₋₂ alkyl.    -   (46) R_(1x) is hydrogen.    -   (47) R_(2a), R_(2b), R_(2c) and R_(2d) are independently        selected from hydrogen, cyano, halo or a group of the formula:

-L_(2a)-L_(2b)-Q₂

-   -   -   wherein        -   L_(2a) is absent or C₁₋₃alkylene optionally substituted by            C₁₋₂ alkyl or oxo;        -   L_(2b) is absent or selected from O, S, N(R_(n)), C(O),            C(O)O, OC(O), C(O)N(R_(n)), N(R_(n))C(O),            N(R_(n))C(O)N(R_(o)), wherein R_(n) and R_(o) are each            independently selected from hydrogen or C₁₋₂alkyl; and        -   Q₂ is hydrogen, cyano, C₁₋₆alkyl, C₃₋₆cycloalkyl, aryl,            heterocyclyl or heteroaryl, each of which is optionally            substituted by one or more substituents selected from halo,            trifluoromethyl, trifluoromethoxy, amino, cyano, hydroxy,            amino, carboxy, carbamoyl, sulphamoyl, C₁₋₄alkyl,            NR_(p)R_(q), OR_(p), C(O)R_(p), wherein R_(p) and R_(q) are            each independently selected from hydrogen or C₁₋₄alkyl.

    -   (48) R_(2a), R_(2b), R_(2c) and R_(2d) are independently        selected from hydrogen, cyano, halo or a group of the formula:

-L_(2a)-L_(2b)-Q₂

-   -   -   wherein        -   L_(2a) is absent or C₁₋₃alkylene optionally substituted by            C₁₋₂ alkyl;        -   L_(2b) is absent or selected from O, S, N(R_(n)), C(O); and        -   Q₂ is hydrogen, cyano, C₁₋₆alkyl, C₃₋₆cycloalkyl, aryl,            heterocyclyl or heteroaryl, each of which is optionally            substituted by one or more substituents selected from halo,            trifluoromethyl, trifluoromethoxy, amino, cyano and hydroxy.

    -   (49) R_(2a), R_(2b), R_(2c) and R_(2d) are independently        selected from hydrogen, cyano, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy,        halo, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₆cycloalkyl, aryl,        heterocyclyl or heteroaryl, each of which is optionally        substituted by one or more substituents selected from halo,        trifluoromethyl, trifluoromethoxy, amino, cyano and hydroxy.

    -   (50) R_(2a), R_(2b), R_(2c) and R_(2d) are independently        selected from hydrogen, cyano, halo or C₁₋₃alkyl.

    -   (51) R_(2a), R_(2b), R_(2c) and R_(2d) are independently        selected from hydrogen or halo.

    -   (52) R_(2a), R_(2b), R_(2e) and R_(2d) are hydrogen.

    -   (53) R_(3a1), R_(3b1), R_(3c1), R_(3d1), R_(3e1), R_(3f1),        R_(3g1), R_(3h1), R_(3i1), R_(3j1), R_(3k1), R_(3l1), R_(3m1),        R_(3n1), R_(3o1), R_(3p1), R_(3q1), R_(3r1) and R_(3s1) are        independently selected from hydrogen, C₁₋₆alkyl, C₃₋₄        cycloalkyl, hydroxy, and halo; and wherein C₁₋₆alkyl, or C₃₋₄        cycloalkyl is optionally substituted with one or more        substituents selected from halo, amino, cyano, and hydroxy; and        R_(3a2), R_(3b2), R_(3c2), R_(3d2), R_(3e2), R_(3f2), R_(3g2),        R_(3h2), R_(3i2), R_(3j2), R_(3k2), R_(3l2), R_(3m2), R_(3n2),        R_(3o2), R_(3p2) R_(3q2), R_(3r2) and R_(3s2) are hydrogen;

    -   (54) R_(3a1), R_(3b1), R_(3c1), R_(3d1), R_(3e1), R_(3f1),        R_(3g1), R_(3h1), R_(3i1), R_(3j1), R_(3k1), R_(3l1), R_(3m1),        R_(3n1), R_(3o1), R_(3p1), R_(3q1), R_(3r1) and R_(3s1) are        independently selected from hydrogen and C₁₋₆alkyl; and wherein        C₁₋₆alkyl is optionally substituted with one or more hydroxy        substituents;

    -   (55) R_(3a1), R_(3b1), R_(3c1), R_(3d1), R_(3e1), R_(3f1),        R_(3g1), R_(3h1), R_(3i1), R_(3j1), R_(3k1), R_(3l1), R_(3m1),        R_(3n1), R_(3o1), R_(3p1), R_(3q1), R_(3r1) and R_(3s1) are        independently selected from hydrogen and methyl; and wherein        methyl is optionally substituted with one or more hydroxy        substituents;

    -   (56) R_(3a1), R_(3b1), R_(3c1), R_(3d1), R_(3e1), R_(3f1),        R_(3g1), R_(3h1), R_(3i1), R_(3j1), R_(3k1), R_(3l1), R_(3m1),        R_(3n1), R_(3o1), R_(3p1), R_(3q1), R_(3r1) and R_(3s1) are        independently selected from hydrogen and methyl; and wherein        methyl is substituted with a hydroxy substituent;

    -   (57) R_(3a2), R_(3b2), R_(3c2), R_(3d2), R_(3e2), R_(3f2),        R_(3g2), R_(3h2), R_(3i2), R_(3j2), R_(3k2), R_(3l2), R_(3m2),        R_(3n2), R_(3o2), R_(3p2), R_(3q2), R_(3r2) and R_(3s2) are        hydrogen;

    -   (58) R_(3a1) and R_(3a2), R_(3b1) and R_(3b2), R_(3c1) and        R_(3c2), R_(3d1) and R_(3d2), R_(3e1) and R_(3e2), R_(3f1) and        R_(3f2), R_(3g1) and R_(3g2), R_(3h1) and R_(3h2), R_(3i1) and        R_(3i2), R_(3j1) and R_(3j2), R_(3k1) and R_(3k2), R_(3l1) and        R_(3l2), R_(3m1) and R_(3m2), R_(3n1) and R_(3n2), R_(3o1) and        R_(3o2), R_(3p1) and R_(3p2), R_(3q1) and R_(3q2), R_(3r1) and        R_(3r2), and R_(3s1) and R_(3s2) are hydrogen.

    -   (59) R_(3a1) and R_(3a2), R_(3b1) and R_(3b2), R_(3c1) and        R_(3c2), R_(3d1) and R_(3d2), R_(3e1) and R_(3e2), R_(3f1) and        R_(3f2), R_(3g1) and R_(3g2), R_(3h1) and R_(3h2), R_(3i1) and        R_(3i2), R_(3j1) and R_(3j2), R_(3k1) and R_(3k2), R_(3l1) and        R_(3l2), R_(3m1) and R_(3m2), R_(3n1) and R_(3n2), R_(3o1) and        R_(3o2), R_(3p1) and R_(3p2), and R_(3q1) and R_(3q2), R_(3r1)        and R_(3r2), and R_(3s1) and R_(3s2) are linked to form a        spiro-fused C₃₋₄cycloalkyl which is optionally substituted with        one or more substituents selected from halo, amino, cyano, and        hydroxy

    -   (60) n is 0, 1 or 2;

    -   (61) n is 1 or 2;

    -   (62) n is 1;

    -   (63) Y is

wherein R_(3a1), R_(3a2) and n are as herein defined;

-   -   (64) Y is

wherein n is herein defined;

-   -   (65) Y is

wherein R_(3b1), R_(3b2) and n are as herein defined;

-   -   (66) Y is

wherein R_(3c1), R_(3c2) and n are as herein defined;

-   -   (67) Y is

wherein R_(3d1), R_(3d2) and n are as herein defined;

-   -   (68) Y is

wherein R_(3e1), R_(3e2) and n are as herein defined;

-   -   (69) Y is

-   -   (70) Y is

wherein R_(3f1), R_(3f2) and n are as herein defined;

-   -   (71) Y is

wherein R_(3g1), R_(3g2) and n are as herein defined;

-   -   (72) Y is

wherein R_(3h1), R_(3h2) and n are as herein defined

-   -   (73) Y is

wherein R_(3i1), R_(3i2) and n are as herein defined;

-   -   (74) Y is

wherein R_(3j1), R_(3j2) and n are as herein defined;

(75) Y is

wherein R_(3k1), R_(3k2) and n are as herein defined:

-   -   (76) Y is

wherein R_(3l1), R_(3l2) and n are as herein defined;

-   -   (77) Y is

wherein R_(3m1), R_(3m2) and n are as herein defined;

-   -   (78) Y is

wherein R_(3n1), R_(3n2) and n are as herein defined;

-   -   (79) Y is

wherein R_(3o1), R_(3o2) and n are as herein defined;

-   -   (80) Y is

wherein R_(3p1), R_(3p2) and n are as herein defined;

-   -   (81) Y is

wherein R_(3q1), R_(3q2) and n are as herein defined:

-   -   (82) Y is

wherein R_(3r1), R_(3r2) and n are as herein defined;

-   -   (83) Y is

wherein R_(3s1), R_(3s2) and n are as herein defined;

-   -   (84) Y is selected from:

-   -   (85) Y is selected from:

wherein R_(3a1), R_(3a2), R_(3b1), R_(3b2), R_(3e1), R_(3e2), R_(3i1),R_(3i2), R_(3j1) and R_(3j2) are as defined herein.

-   -   (86) Y is selected from:

-   -   (87) Y is selected from:

-   -   (88) Y is selected from

(89) Y is

-   -   (90) R₄, R₅ and R₆ are independently selected from hydrogen and        halo;    -   (91) R₄, R₅ and R₆ are hydrogen;    -   (92) when Z is

then R₇, R₉ and R_(11N) are independently selected from hydrogen, haloand cyano;

-   -   (93) when Z is

then R₇, R₉ and R_(11N) are hydrogen;

-   -   (94) when Z is

then R₈, R₉, R₁₀ and R₁₁ are independently selected from hydrogen, NH₂,halo, cyano, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, C₁₋₆ alkyl, —CH₂OCH₃,—CH₂SO₂CH₃, —SO₂CH₃, —NHC(O)CH₃ and —C(O)NR_(v1)R_(v2), wherein R_(v1)and R_(v2) are independently selected from hydrogen and methyl; oreither R₉ and R₁₀ may be linked together to form a fused 5- or6-membered saturated or unsaturated ring system or R₁₀ and R₁₁ may belinked together to form a fused 5- or 6-membered saturated orunsaturated ring system.

-   -   (95) when Z is

then R₈, R₉, R₁₀ and R₁₁ are independently selected from hydrogen, NH₂,halo, cyano, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy and C₁₋₃ alkyl.

-   -   (95a) when Z is

then R₈ is selected from hydrogen, cyano, —CH₂OCH₃, —CH₂SO₂CH₃, —SO₂CH₃,—NHC(O)CH₃ and —C(O)NR_(v1)R_(v2), wherein R_(v1) and R_(v2) areindependently selected from hydrogen and methyl; R₉ is hydrogen; R₁₀ isselected from halo, C₁₋₄alkoxy or C₁₋₄haloalkoxy; and R₁ is hydrogen.

-   -   (96) when Z is

then R₈ is hydrogen, cyano, —CH₂OCH₃, —CH₂SO₂CH₃, —SO₂CH₃, —NHC(O)CH₃and —C(O)NR_(v1)R_(v2), wherein R_(v1) and R_(v2) are independentlyselected from hydrogen and methyl; R₉ is hydrogen; R₁₀ is C₁₋₄alkoxy orC₁₋₄haloalkoxy; and R₁₁ is hydrogen.

-   -   (97) when Z is

then R₈ is hydrogen or cyano; R₉ is hydrogen; R₁₀ is C₁₋₄alkoxy; and R₁₁is hydrogen.

-   -   (97a) when Z is

then R₈, R₉ and R₁₁ are hydrogen, and R₁₀ is methoxy.

-   -   (98) when Z is

then R₈, R₉, R₁₀ and R₁₁ are hydrogen.

-   -   (99) R_(Z1) and R_(Z1a) are selected from hydrogen, C₁₋₄alkyl,        cyano, halo, C₁₋₄haloalkyl, C₁₋₄haloalkoxy, C₁₋₄alkoxy,        C₃₋₆cycloalkyl and —O—C₃₋₆cycloalkyl, wherein C₃₋₆cycloalkyl and        —O—C₃₋₆cycloalkyl are optionally substituted by one or more of        halo, methyl or methoxy;    -   (100) R_(Z1) and R_(Z1a) are selected from hydrogen, C₁₋₂alkyl,        cyano, halo, C₁₋₂haloalkyl, C₁₋₂haloalkoxy, C₁₋₂alkoxy;    -   (101) R_(Z1) and R_(Z1a) are selected from hydrogen, C₁₋₂alkyl,        cyano and halo;    -   (102) R_(Z1) and R_(Z1a) are hydrogen;    -   (103) R_(Z2), R_(Z2a), R_(Z3a), R_(Z1e) and R_(Z2e) are        independently selected from hydrogen, C₁₋₄alkyl, cyano, halo or        C₁₋₄alkoxy;    -   (104) R_(Z2), R_(Z2a), R_(Z3a), R_(Zi1b) and R_(Zi2e) are        independently selected from hydrogen, cyano or halo;    -   (105) R_(Z2), R_(Z2a), R_(Z3a), R_(Zi1b) and R_(Zi2e) are        hydrogen;    -   (106) R_(B5N), R_(Y5N), R_(Z2N) and R_(11N) are selected from        hydrogen or methyl;    -   (107) R_(B5N), R_(Y5N), R_(Z2N) and R_(11N) are hydrogen;    -   (108) R_(Z4), R_(Z5), R_(Z6), R_(Z7), R_(Z8), R_(Z9), R_(Z10),        R_(Z11), R_(Z12), R_(Z13), R_(Z14), R_(Z15), and R_(Z16) are        independently selected from hydrogen, halo and cyano;    -   (109) R_(Z4), R_(Z5), R_(Z6), R_(Z7), R_(Z8), R_(Z9), R_(Z10),        R_(Z11), R_(Z12), R_(Z13), R_(Z14), R_(Z15) and R_(Z16) are        independently selected from hydrogen and halo;    -   (110) R_(Z4), R_(Z5), R_(Z6), R_(Z7), R_(Z8), R_(Z9), R_(Z10),        R_(Z11), R_(Z12), R_(Z13), R_(Z14), R_(Z15), R_(Z16) are        hydrogen;    -   (111) Suitably,        -   when X₆ is A₁, A₁ is CR₁₂;        -   when X₇ is A₂, A₂ is CR₁₃;        -   B₁ is A₅, wherein A₅ is CR₁₆;        -   B₂ is A₆, wherein A₆ is CR₁₇;        -   Y₂ is A₇, wherein is CR₁₈;        -   when X₆ is A₈, A₈ is CR₁₉R₂₀;        -   when X₇ is A₉, A₉ is CR₂₂R₂₃;        -   when X₇ is A₁₁, A₁₁ is CR₂₈R₂₉;        -   and wherein R₁₂, R₁₃, R₁₆, R₁₇, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂,            R₂₃, R₂₈ and R₂₉ are as defined herein.    -   (112) R₁₂, R₁₃, R₁₆, R₁₉, R₂₀, R₂₁, R₂₂ and R₂₃ are        independently selected from hydrogen, halo, cyano and methyl;    -   (113) R₁₂, R₁₃, R₁₆, R₁₉, R₂₀, R₂₁, R₂₂ and R₂₃ are hydrogen;    -   (114) R₁₂ is selected from hydrogen, halo, cyano and C₁₋₄ alkyl;    -   (115) R₁₂ is selected from hydrogen and halo;    -   (116) R₁₂ is selected from hydrogen and chloro;    -   (117) R₁₂ is hydrogen;    -   (118) R₁₃ is selected from hydrogen, halo, cyano and methyl;    -   (119) R₁₃ is hydrogen;    -   (120) R₁₃ is selected from hydrogen, methoxy and methyl;    -   (121) R₁₆ and R₁₈ are selected from hydrogen, halo, cyano, C₁₋₄        alkyl, C₁₋₄ alkoxy, C₁₋₄haloalkyl and C₁₋₄haloalkoxy;    -   (122) R₁₆ and R₁₈ are selected from hydrogen, halo, cyano and        C₁₋₄ alkyl;    -   (123) R₁₆ and R₁₈ are selected from hydrogen and halo;    -   (124) R₁₆ and R₁₈ are hydrogen;    -   (125) R₁₇ is selected from hydrogen, halo, cyano, C₁₋₅ alkyl,        C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, C₂₋₄ alkenyl, C₂₋₄        alkynyl, phenyl, a 5- or 6-membered or heteroaryl,        C₃₋₆cycloalkyl, —O—C₃₋₆cycloalkyl, heterocyclyl, —O-heterocyclyl        (carbon-linked), —(OCH₂CH₂)_(m)—OCH₃ wherein m is an integer        from 1 to 6, NR_(q)R_(r), wherein R_(q) and R_(r) are each        independently hydrogen, C₁₋₄ alkyl, C₃₋₆cycloalkyl, a 3- to        6-membered carbon-linked heterocyclyl, or R_(q) and R_(r) are        linked together such that, together with the nitrogen atom to        which they are attached, they form a 3- to 6-membered        heterocyclic ring;        -   wherein any C₁₋₅alkyl, C₁₋₄ alkoxy, C₂₋₄alkenyl,            C₂₋₄alkynyl, phenyl, 5- or 6-membered or heteroaryl,            C₃₋₆cycloalkyl, —O—C₃₋₆cycloalkyl, heterocyclyl or            —O-heterocyclyl (carbon-linked) is optionally further            substituted by one or more substituents selected from            C₁₋₂alkyl, cyano, C₁₋₂haloalkyl, hydroxy, C₁₋₂alkoxy, halo,            C₁₋₂haloalkoxy, NR_(1ea)R_(1fa) or —S(O)₀₋₂R_(1ea)R_(1fa),            wherein R_(1ea) and R_(1fa) are H or C₁₋₂alkyl.    -   (126) R₁₇ is selected from hydrogen, halo, cyano, C₁₋₂ alkyl,        C₁₋₂ haloalkyl, C₁₋₂ alkoxy, C₁₋₂ haloalkoxy, C₂₋₃ alkenyl, C₂₋₃        alkynyl, phenyl a 5- or 6-membered or heteroaryl,        C₃₋₆cycloalkyl, —O—C₃₋₆cycloalkyl, heterocyclyl, —O-heterocyclyl        (carbon-linked), —(OCH₂CH₂)_(m)—OCH₃ wherein m is an integer        from 1 to 6, NR_(q)R_(r), wherein R_(q) and R_(r) are each        independently hydrogen, C₁₋₂ alkyl or R_(q) and R_(r) are linked        together such that, together with the nitrogen atom to which        they are attached, they form a 3- to 6-membered heterocyclic        ring;        -   wherein any C₁ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, phenyl, 5-            or 6-membered or heteroaryl, C₃₋₆cycloalkyl,            —O—C₃₋₆cycloalkyl, heterocyclyl or —O-heterocyclyl            (carbon-linked) is optionally further substituted by one or            more substituents selected from C₁₋₂alkyl, cyano,            C₁₋₂haloalkyl, hydroxy, C₁₋₂alkoxy, halo, C₁₋₂haloalkoxy,            NR_(1ea)R_(1f)a or —S(O)₀₋₂R_(1ea)R_(1fa), wherein R_(1ea)            and R_(1fa) are H or C₁₋₂alkyl.    -   (127) R₁₇ is selected from hydrogen, halo, cyano, C₁₋₄ alkyl,        C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, C₂₋₄ alkenyl, C₂₋₄        alkynyl, phenyl, a 5- or 6-membered heteroaryl, C₃₋₆cycloalkyl,        —O—C₃₋₆cycloalkyl, heterocyclyl, —O-heterocyclyl        (carbon-linked), —(OCH₂CH₂)_(m)—OCH₃ wherein m is 1, 2 or 3,        NR_(q)R_(r), wherein R_(q) and R_(r) are each independently        hydrogen, C₁₋₄ alkyl; or R_(q) and R_(r) are linked together        such that, together with the nitrogen atom to which they are        attached, they form a 3- to 6-membered heterocyclic ring;        -   wherein any C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, phenyl,            5- or 6-membered or heteroaryl, C₃₋₆cycloalkyl,            —O—C₃₋₆cycloalkyl, heterocyclyl or —O-heterocyclyl            (carbon-linked) is optionally further substituted by one or            more substituents selected from C₁₋₂alkyl, C₁₋₂haloalkyl,            cyano, hydroxy, C₁₋₂alkoxy, halo and C₁₋₂haloalkoxy.    -   (128) R₁₇ is selected from hydrogen, halo, cyano, C₁₋₄ alkyl,        C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, C₂₋₄ alkenyl, C₂₋₄        alkynyl, C₃₋₆cycloalkyl, —O—C₃₋₄cycloalkyl, heterocyclyl,        —(OCH₂CH₂)_(m)—OCH₃ wherein m is 1, 2 or 3, NR_(q)R_(r), wherein        R_(q) and R_(r) are each independently hydrogen or C₁₋₂ alkyl;        -   wherein any C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,            C₃₋₆cycloalkyl, —O—C₃₋₄cycloalkyl, heterocyclyl, system is            optionally further substituted by one or more substituents            selected from C₁₋₂alkyl, C₁₋₂haloalkyl, cyano, hydroxy,            C₁₋₂alkoxy, halo and C₁₋₂haloalkoxy.    -   (129) R₁₇ is selected from hydrogen, halo, cyano, C₁₋₄ alkyl,        C₁₋₄ alkoxy, C₂₋₄ alkenyl, C₂₋₄ alkynyl and a 5- or 6-membered        aryl or heteroaryl; wherein any C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄        alkynyl, 5- or 6-membered aryl or heteroaryl is optionally        further substituted by one or more substituents selected from        C₁₋₂alkyl, C₁₋₂haloalkyl, cyano, hydroxy, C₁₋₂alkoxy, halo and        C₁₋₂haloalkoxy.    -   (130) R₁₇ is selected from hydrogen, halo, C₁₋₄ alkoxy, C₂₋₄        alkynyl and 5- or 6-membered aryl or heteroaryl.    -   (131) R₁₇ is selected from hydrogen, C₁₋₄ alkoxy, bromo,        ethynyl, and pyrazoly.    -   (132) R₂₈ and R₂₉ are selected from hydrogen or halo, methoxy        and methyl;    -   (133) R₂₈ and R₂₉ are hydrogen;    -   (134) R₂₁, R₂₄ and R₃₀, are independently selected from hydrogen        or methyl;    -   (135) R₂₁, R₂₄ and R₃₀, are hydrogen;    -   (136) Z is selected from

wherein X₂, X₃, X₄, X₅, X₆, X₇, X₈ and X₉ are as defined herein;

-   -   (137) Z is

-   -   -   wherein X₂, X₄, X₅, X₆, X₇, X₈ and X₉ are as defined herein;

    -   (138) Z is

-   -   -   X₂ is CR₄:        -   X₄ is C or N;        -   X₅ is CR₅:        -   X₆ is A₁, wherein A₁ is CR₁₂        -   X₇ is A₂, wherein A₂ is CR₁₃        -   X₈ is N or CR₆,        -   X₉ is N or C;        -   wherein R₄, R₅, R₆, R₁₂ and R₁₃ are as defined herein;

    -   (139) Z is

wherein R₄, R₅, R₆, A₁ and A₂ are as herein defined;

-   -   (140) Z is

-   -   -   wherein X₂, X₄, X₅, X₆, X₇, X₈ and X₉ are as defined herein;

    -   (141) Z is

-   -   -   X₂ is CR₄:        -   X₄ is N;        -   X₅ is CR₅:        -   X₆ is A₁, wherein A₁ is CR₁₂        -   X₇ is A₂, wherein A₂ is CR₁₃        -   X₈ is CR₆,        -   X₉ is N or C;        -   wherein R₄, R₅, R₆, R₁₂, R₁₃, X₇, X₈ and X₉ are as defined            herein;

    -   (142) Z is

wherein R₄, R₅, R₆, A₁ and A₂ are as herein defined;

-   -   (143) Z is

-   -   -   wherein B₁, B₂, B₃, B₄, B₅, B₇ and B₈ are as defined herein;

    -   (144) Z is:

-   -   -   wherein        -   B₁ is A₅, wherein A₅ is N or CR₁₆;        -   B₂ is A₆, wherein A₆ is CR₁₇        -   B₃ is N or CR_(Z1);        -   B₄ is N or C;        -   B₅ is selected from CR_(zi1b) or NR_(B5N)        -   B₇ is N, NR_(Z2N) or CR_(Z2);        -   B₈ is selected from C or N;        -   wherein R₁₆, R₁₇, R_(Z1), R_(zi1b), R_(B5N), R_(Z2) are as            defined herein;

    -   (145) Z is:

-   -   -   wherein        -   B₁ is A₅, wherein A₅ is CR₁₆;        -   B₂ is A₆, wherein A₆ is CR₁₇        -   B₃ is CR_(Z1);        -   B₄ is N or C;        -   B₅ is selected from CR_(zi1b) or NR_(B5N)        -   B₇ is N, NH or CR_(Z2);        -   B₈ is C;        -   wherein R₁₆, R₁₇, R_(Z1), R_(zi1b), R_(B5N), R_(Z2) are as            defined herein;

    -   (146) Z is

wherein A₅, A₆, R_(Z1) and R_(Z2) are as herein defined;

-   -   (147) Z is

wherein A₅, A₆, R_(Z1), R_(Z2) are R_(Zi1b) are as herein defined;

-   -   (148) Z is

wherein A₅, A₆, R_(Z1), R_(Z2N) are R_(Zi1b) are as herein defined;

-   -   (149) Z is:

wherein R_(Z1), R_(Z2), R_(Zi1b), A₅ and A₆ are as herein defined;

-   -   (150) Z is:

wherein R_(Z2), A₅ and A₆ are as herein defined;

-   -   (151) Z is:

wherein R_(Z1d), R_(Z2d) and A₆ are as herein defined;

-   -   (152) Z is

-   -   -   wherein Q₇, Q₈, Q₉, Q₁₀ and Q₁₁ are as defined herein;

    -   (153) Z is

-   -   -   wherein Q₈, Q₉, Q₁₀ and Q₁₁ are as defined herein;

    -   (154) Z is selected from:

-   -   -   wherein R₇, R₈, R₉, R₁₀ and R₁₁ are as defined herein:

    -   (155) Z is

wherein R₈, R₉, R₁₀ and R₁₁ are as herein defined;

-   -   (156) Z is

wherein:

-   -   -   R₈ is selected from hydrogen, cyano, —CH₂OCH₃, —CH₂SO₂CH₃,            —SO₂CH₃, —NHC(O)CH₃ and —C(O)NR_(v1)R_(v2), wherein R_(v1)            and R_(v2) are independently selected from hydrogen and            methyl        -   R₁₀ is selected from halo, C₁₋₄alkoxy or C₁₋₄haloalkoxy;        -   R₉ and R₁₁ are as herein defined;

    -   (157) Z is

wherein R₈ is hydrogen or cyano and R₁₀ is C₁₋₄alkoxy;

-   -   (157a) Z is

-   -   (158) Z is

-   -   (159) Z is

wherein A₇, R_(Y5N), R_(Z1a), R_(Z2a) and R_(Z3)a are as herein defined;

-   -   (160) Z is

wherein R₄, R₅, A₈ and A₉ are as herein defined;

-   -   (161) Z in

wherein R₄, R₅, R₆, A₈ and A₁₁ are as herein defined;

-   -   (162) Z is

-   -   -   wherein Q₈, Q₉, Q₁₀ and Q_(11a) are as defined herein;

    -   (163) Z is

wherein R₇, R₉ and R_(11N) are as herein defined;

-   -   (164) Z is

-   -   -   wherein        -   X₁ is N or CR_(Z9);        -   X₂ is CR₄:        -   X₃ is N;        -   X₄ is C;        -   X₅ is CR₅:        -   X₆ is A₁, wherein A₁ is CR₁₂        -   X₇ is A₂, wherein A₂ is CR₁₃        -   X₈ is N or CR₆,        -   X₉ is N or C;        -   wherein R_(Z9), R₄, R₅, R₆, R₁₂ and R₁₃ are as defined            herein.

    -   (165) Z is

-   -   -   wherein        -   Y₂ is A₇, wherein A₇ is CR₁₈;        -   Y₃ is N or CR_(Z1a);        -   Y₄ is C or N        -   Y₅ is NR_(Y5N);        -   Y₆ is C—R_(Zi2e) or N;        -   Y₇ is CR_(Z2a) or N;        -   Y₈ is C or N;        -   Y₉ is CR_(Z3a) or N;        -   wherein R₁₈, R_(z1a), R_(Y5N), R_(Zi2e), R_(Z2a) and R_(Z3a)            are as defined herein;

    -   (166) Z is

-   -   -   wherein        -   Y₂ is A₇, wherein A₇ is CR₁₈;        -   Y₄ is C or N        -   Y₅ is NR_(Y5N);        -   Y₆ is C—R_(Zi2e) or N;        -   Y₇ is CR_(Z2a) or N;        -   Y₈ is C or N;        -   Y₉ is CR_(Z3a) or N;        -   wherein R₁₈, R_(z1a), R_(Y5N), R_(Zi2e), R_(Z2a) and R_(Z3a)            are as defined herein;

    -   (167) Z is:

wherein R_(Y5N), R_(Z1a), R_(Z2a), R_(Z3a) and A₇ are as herein defined;

-   -   (168) Z is:

wherein R_(Z1a), R_(Z2a), R_(Z3a) and A₇ are as herein defined;

-   -   (169) Z is:

wherein R_(Y5N), R_(Z2a), R_(Z3a), R_(Zi2e) and A₇ are as hereindefined;

-   -   (170) Z is:

wherein R_(Z2a), R_(Z3a), R_(Zi2e) and A₇ are as herein defined;

-   -   (171) Z is

-   -   -   wherein,        -   Y₂ is A₇, wherein A₇ is CR₁₈;        -   Y₄ is N        -   Y₅ is C—R_(Y5);        -   Y₆ is C—R_(Zi2e);        -   Y₇ is O or S;        -   Y₈ is C;        -   Y₉ is N;        -   wherein R₁₈, R_(Y5), R_(Zi2e) are as defined herein;

    -   (172) Z is:

-   -   -   wherein A₇ and R_(Zi2e) are as defined herein;

    -   (173) Z is:

wherein R₄, R₅, R₆, R_(Z9), R₁₂ and R₁₃ are as herein defined:

-   -   (174) Z is:

wherein R₄, R₅, R₆, R₁₉, R₂₂ and R_(Z9) are as herein defined;

-   -   (175) Z is

-   -   -   wherein X₂, X₃, X₄, X₅, X₆, X₇, X₈ and X₉ are as defined            herein;

    -   (176) Z is:

wherein R₄, R₅, R₆, R₁₂, R₁₃ and R_(Z9) are as herein defined;

-   -   (177) Z is        -   wherein Z₁₀, Z₁₁, Z₁₂, Z₁₃, Z₁₄, Z₁₅ and Z₁₆ are as defined            herein;    -   (178) Z is

-   -   -   wherein        -   Z₁₀ is CR_(Z10),        -   Z₁₁ is N;        -   Z₁₂ is CR_(Z12);        -   Z₁₃ is CR_(Z13);        -   Z₁₄ is N or CR_(Z14);        -   Z₁₅ is N or CR_(Z15);        -   Z₁₆ is CR_(Z16);        -   wherein R_(Z10), R_(Z12), R_(Z13), R_(Z14), R_(Z15) and            R_(Z16) are as defined herein;

    -   (179) Z is

-   -   -   wherein        -   Z₁₀ is CR_(Z10),        -   Z₁₁ is CR_(Z10) or N;        -   Z₁₂ is CR_(Z12);        -   Z₁₃ is CR_(Z13);        -   Z₁₄ is N;        -   Z₁₅ is N or CR_(Z15);        -   Z₁₆ is CR_(Z16);        -   wherein R_(Z10), R_(Z12), R_(Z13), R_(Z14), R_(Z15) and            R_(Z16) are as defined herein;

    -   (180) Z is:

wherein Z₁₀, Z₁₂, Z₁₃, Z₁₄, Z₁₅ and Z₁₆ are as herein defined;

-   -   (181) Z is:

wherein Z₁₃, Z₁₄, Z₁₅ and Z₁₆ are as herein defined;

-   -   (182) Z is:

wherein R_(Z10), R_(Z12), R_(Z13), R_(Z14), R_(Z15) and R_(Z16) are asherein defined;

-   -   (183) Z is:

wherein Z₁₀, Z₁₁, Z₁₂, Z₁₃, Z₁₅ and Z₁₆ are as herein defined,

-   -   (184) Z is:

wherein R_(Z10a), R_(Z11a), R_(Z12a), R_(Z13a), R_(Z15a) and R_(Z16)aare as herein defined;

-   -   (185) Z is selected from:

-   -   -   wherein B₁, B₂, B₃, B₄, B₅, B₇, B₈, Y₂, Y₃, Y₄, Y₅, Y₆, Y₇,            Y₈, Y₉, X₁, X₂, X₃, X₄, X₅, X₆, X₇, X₈ and X₉ are as defined            herein;

    -   (186) Z is selected from:

-   -   -   wherein:        -   A₁, A₂, A₅, A₆, A₇, A₈, A₉, A₁₁, R₄, R₅, R₆, R₇, R₈, R₉,            R₁₀, R₁₁, R_(11N), R₁₂, R₁₃, R₁₉, R₂₂, R_(Y5N), R_(Z1),            R_(Z2), R_(Z9), R_(Z10), R_(Z11), R_(Z12), R_(Z13), R_(Z14),            R_(Z15), R_(Z16), R_(Z2a), R_(Z3a), R_(Z1a), R_(Zi1b) and            R_(Zi2e) are as defined herein;

    -   (187) Z is selected from:

-   -   -   wherein A₁, A₂, A₅, A₆, A₇, A₈, A₉, A₁₁, R₄, R₅, R₆, R₇, R₈,            R₉, R₁₀, R₁₁, R_(11N), R₁₂, R₁₃, R₁₉, R₂₂, R_(Z1), R_(Z2),            R_(Z9), R_(Z10), R_(Z11), R_(Z12), R_(Z13), R_(Z14),            R_(Z15), R_(Z16), R_(Z2a), R_(Z3a), R_(Z1a), R_(Zi1b) and            R_(Zi2e) are as defined herein;

    -   (188) Z is selected from:

-   -   -   A₁, A₂, A₅, A₆, A₇, A₈, A₉, A₁₁, R₄, R₅, R₆, R₇, R₈, R₉,            R₁₀, R₁₁, R_(Y5N), R_(Z1), R_(Z2), R_(Z10), R_(Z12),            R_(Z13), R_(Z14), R_(Z15), R_(Z16), R_(Z2a), R_(Z3a),            R_(Z1a), R_(Zi1b) and R_(Zi2e) are as defined herein;

    -   (189) Z is selected from:

wherein A₁, A₂, A₅, A₆, A₇, A₈, A₉, A₁₁, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀,R₁₁, R_(Y5N), R_(Z1), R_(Z2), R_(Z10), R_(Z12), R_(Z13), R_(Z14),R_(Z15), R_(Z16), R_(Z2a), R_(Z3a), R_(Z1a), R_(Zi1b) and R_(Zi2e) areas defined herein.

-   -   (190) Z is selected from:

wherein A₁, A₂, A₅, A₆, A₇, A₈, A₉, A₁₁, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀,R₁₁, R_(Y5N), R_(Z1), R_(Z2), R_(Z10), R_(Z12), R_(Z13), R_(Z14),R_(Z15), R_(Z16), R_(Z2a), R_(Z3a), R_(Z1a), R_(Zi1b) and R_(Zi2e) areas defined herein.

-   -   (191) Z is selected from:

wherein R₈, R₁₀, R₁₇, R₁₈ and R_(Z1), are as defined herein.

-   -   (192) Z is selected from:

-   -   (193) Z is selected from:

Suitably, a heteroaryl or heterocyclyl group as defined herein is amonocyclic heteroaryl or heterocyclyl group comprising one, two or threeheteroatoms selected from N, O or S.

Suitably, a heteroaryl is a 5- or 6-membered aryl or heteroaryl ringcomprising one, two or three heteroatoms selected from N, O or S.

Suitably, a heterocyclyl group is a 4-, 5- or 6-membered heterocyclylring comprising one, two or three heteroatoms selected from N, O or S.Most suitably, a heterocyclyl group is a 5- or 6-membered ringcomprising one, two or three heteroatoms selected from N, O or S [e.g.morpholinyl (e.g. 4-morpholinyl), oxetane, methyloxetane (e.g.3-methyloxetane), pyrrolidinone (e.g. pyrrolidin-2-one)].

Suitably, an aryl group is phenyl.

In an embodiment, X is

Y is selected from:

and

Z is selected from:

wherein:

-   -   (i) R_(1a), R_(1b), R_(2a), R_(2b) and R_(2d) are as defined        herein;    -   (ii) R_(3a1), R_(3a2), R_(3b1), R_(3b2), R_(3i1), R_(3i2),        R_(3j1), R_(3j2) and n are as defined herein; and    -   (iii) A₁, A₂, A₅, A₆, A₇, R₄, R₅, R₆, R₈, R₉, R₁₀, R₁₁, R_(Z1),        R_(Z2), R_(Z10), R_(Z12), R_(Z13), R_(Z14), R_(Z15), R_(Z16),        R_(Z2a), R_(Z3a), R_(Zi2e), R_(Zi1b) and R_(Z2) are as defined        herein.

In an embodiment,

X is

Y is

Z is

wherein:

-   -   (i) R_(1a), R_(1b), R_(2a), R_(2b) and R_(2d) are as defined        herein;    -   (ii) n, R_(3a1), R_(3a2), R_(3j1), R_(3j2), are as defined        herein; and    -   (iii) A₁, A₂, A₅, A₆, A₇, R₄, R₅, R₆, R₈, R₉, R₁₀, R₁₁, R_(Z1),        R_(Z2), R_(Z2a), R_(Z3a), R_(Zi2e), R_(Zi1b) are as defined        herein.

In an embodiment,

X is

Y is

Z is

wherein:

-   -   (i) R_(1a), R_(1b), R_(2a), R_(2b) and R_(2d) are as defined        herein;    -   (ii) n, R_(3a1) and R_(3a2), are as defined herein; and    -   (iii) A₁, A₂, A₅, A₆, A₇, R₄, R₅, R₆, R₈, R₉, R₁₀, R₁₁, R_(Z1),        R_(Z2), R_(Z2a), R_(Z3a), R_(Zi2e), R_(Zi1b) are as defined        herein.

In an embodiment:

X is

Y is

and

Z is

wherein:

-   -   (i) R_(1a), R_(1b), R_(2a), R_(2b) and R_(2d) are as defined        herein;    -   (ii) n, R_(3j1) and R_(3j2) are as defined herein; and    -   (iii) A₁, A₂, A₅, A₆, A₇, R₄, R₅, R₆, R₈, R₉, R₁₀, R₁₁, R_(Z1),        R_(Z2), R_(Z2a), R_(Z3a), R_(Zi2e), R_(Zi1b) are as defined        herein.

In an embodiment,

X is

Y is

Z is

(i) wherein R_(1a), R_(1b), R_(2a), R_(2b) and R_(2d) are as definedherein;(ii) n, R_(3a1) and R_(3a2) are as defined herein; and(iii) A₅, A₆, R_(Z1) and R_(Z2) are as defined herein.

In an embodiment,

X is

Y is

and

Z is

(i) wherein R_(1a), R_(1b), R_(2a), R_(2b) and R_(2d) are as definedherein;

(ii) n, R_(3a1) and R_(3a2) are as defined herein; and

(iii) A₁, A₂, R₄, R₅ and R₆ are as defined herein.

In an embodiment,

X is

Y is

and

Z is

(i) wherein R_(1a), R_(1b), R_(2a), R_(2b) and R_(2d) are as definedherein;

(ii) n, R_(3a1) and R_(3a2) are as defined herein; and

(iii) A₅, A₆, R_(Z1), R_(Zi1b), and R_(Z2) are as defined herein.

In an embodiment,

X is

Y is

and

Z is

(i) wherein R_(1a), R_(1b), R_(2a), R_(2b) and R_(2d) are as definedherein;

(ii) n, R_(3a1) and R_(3a2) are as defined herein; and

(iii) A_(Z6), R_(Z2e), R_(Z3e) and R_(Zi2e) are as defined herein.

In an embodiment,

X is

Y is

and

Z is

(i) wherein R_(1a), R_(1b), R_(2a), R_(2b) and R_(2d) are as definedherein;

(ii) n, R_(3a1) and R_(3a2) are as defined herein; and

(iii) A₅, A₆, R_(Z1) and R_(Z2) are as defined herein.

In an embodiment,

X is

Y is

and

Z is

(i) wherein R_(1a), R_(1b), R_(2a), R_(2b) and R_(2d) are as definedherein;

(ii) n, R_(3a1) and R_(3a2) are as defined herein; and

(iii) A₁, A₂, R₄, R₅ and R₆ are as defined herein.

In an embodiment,

X is

Y is

and

Z is

(i) wherein R_(1a), R_(1b), R_(2a) and R_(2d) are as defined herein;

(ii) n, R_(3a1) and R_(3a2) are as defined herein; and

(iii) A₅, A₆, R_(Z1), R_(Z1b), and R_(Z2) are as defined herein.

In an embodiment,

X is

Y is

and

Z is

(iv) wherein R_(1a), R_(1b), R_(2a), R_(2b) and R_(2d) are as definedherein;

(v) n, R_(3a1) and R_(3a2) are as defined herein; and

(vi) A_(Z6), R_(Z2e), R_(Z3e) and R_(Zi2e) are as defined herein.

In an embodiment,

X is

Y is

and

Z is

(i) wherein R_(1a), R_(1b), R_(2a), R_(2b) and R_(2d) are as definedherein;

(ii) n, R_(3j1) and R_(3j2) are as defined herein; and

(iii) A₅, A₆, R_(Z1) and R_(Z2) are as defined herein.

In an embodiment,

X is

Y is

and

Z is

(i) wherein R_(1a), R_(1b), R_(2a), and R_(2d) are as defined herein;

(ii) n, R_(3j1) and R_(3j2) are as defined herein; and

(iii) A₅, A₆, R_(Z1) and R_(Z2) are as defined herein.

In an embodiment,

X is

Y is

and

Z is

(i) wherein R_(1a), R_(1b), R_(2a), R_(2b) and R_(2d) are as definedherein;

(ii) n, R_(3j1) and R_(3j2) are as defined herein; and

(iii) A₁, A₂, R₄, R₅ and R₆ are as defined herein.

In an embodiment,

X is

Y is

and

Z is

(iv) wherein R_(1a), R_(1b), R_(2a) and R_(2d) are as defined herein;

(v) n, R_(3j1) and R_(3j2) are as defined herein; and

(vi) A₁, A₂, R₄, R₅ and R₆ are as defined herein.

In an embodiment,

X is

Y is

and

Z is

(i) wherein R_(1a), R_(1b), R_(2a), R_(2b) and R_(2d) are as definedherein;

(ii) n, R_(3j1) and R_(3j2) are as defined herein; and

(iii) A₅, A₆, R_(Z1), R_(Zi1b), and R_(Z2) are as defined herein

In an embodiment,

X is

Y is

and

Z is

(i) wherein R_(1a), R_(1b), R_(2a), R_(2b) and R_(2d) are as definedherein;

(ii) n, R_(3j1) and R_(3j2) are as defined herein; and

(iii) A₅, A₆, R_(Z1), R_(Zi1b), and R_(Z2) are as defined herein

In an embodiment,

X is

Y is

and

Z is

wherein:

(i) R_(1a), R_(1b), R_(2a), R_(2b) and R_(2d) are as defined herein;

(ii) n, R_(3j1) and R_(3j2) are as defined herein; and

(iii) A₇, R_(Z2a), R_(Z3a) are R_(Zi2e) are as defined herein.

In an embodiment,

X is

Y is

and

Z is

wherein:

(i) R_(1a), R_(1b), R_(2a), R_(2b) and R_(2d) are as defined herein;

(ii) n, R_(3j1) and R_(3j2) are as defined herein; and

(iii) A₇, R_(Z2a), R_(Z3a) are R_(Zi2e) are as defined herein.

In an embodiment,

X is

Y is

and

Z is

wherein:

(iv) R_(1a), R_(1b), R_(2a), R_(2b) and R_(2d) are as defined herein;

(v) n, R_(3j1) and R_(3j2) are as defined herein; and

(vi) R₈, R₉, R₁₀ and R₁₁ are as defined herein.

In an embodiment,

X is

Y is

Z is

wherein:

(iv) R_(1a), R_(1b), R_(2a), R_(2b) and R_(2d) are as defined herein;

(v) n, R_(3a1), R_(3a2), R_(3j1), R_(3j2), are as defined herein; and

(vi) R₈, R₉, R₁₀, R₁₁ are as defined herein.

In an embodiment:

when X₆ is A₁, A₁ is CR₁₂;

when X₇ is A₂, A₂ is CR₁₃;

B₁ is A₅, wherein A₅ is CR₁₆;

B₂ is A₆, wherein A₆ is CR₁₇;

Y₂ is A₇, wherein A₇ is CR₁₈;

when X₆ is A₈, A₈ is CR₁₉R₂₀;

when X₇ is A₉, A₉ is CR₂₂R₂₃;

when X₇ is A₁₁, A₁₁ is CR₂₈R₂₉;

-   -   and wherein R₁₂, R₁₃, R₁₆, R₁₇, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, R₂₃,        R₂₈ and R₂₉ are as defined herein.

In an embodiment: A₁ is CR₁₂; A₂ is CR₁₃; A₅ is CR₁₆; A₆ is CR₁₇; A₇ isCR₁₈; A₈ is CR₁₉R₂₀; A₉ is CR₂₂R₂₃; A₁₁ is CR₂₈R₂₉; wherein R₁₂, R₁₃,R₁₆, R₁₇, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, R₂₃, R₂₈ and R₂₉ are as definedherein

In an embodiment:

-   -   (i) R₄, R₅, R_(X5a), R_(X5b), R_(Y5), R₆, R₇, R₈, R₉, R₁₀, R₁₁,        R_(11a), R_(11b), R_(Z2), R_(Z2a), R_(Z3a), R_(Zi1b), R_(Zi2e),        R_(Z9), R_(Z10), R_(Z11), R_(Z12), R_(Z12a), R_(Z13), R_(Z14),        R_(Z15) and R_(Z16) are independently selected from hydrogen,        methyl, cyano or halo; and    -   R_(B5N), R_(Y5N), R_(Z2N) and R_(11N) are selected from methyl        or hydrogen;    -   (ii) R_(Z1) and R_(Z1a) are selected from hydrogen, C₁₋₄alkyl,        cyano, halo, C₁₋₄haloalkyl, C₁₋₄haloalkoxy, C₁₋₄alkoxy,        C₃₋₆cycloalkyl and —O—C₃₋₆cycloalkyl;    -   (iii) R₁₂, R₁₃, R₁₆, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, R₂₃, R₂₄ and R₃₀        are independently selected from hydrogen, halo, cyano and        methyl;    -   (iv) R₁₇ is selected from hydrogen, halo, cyano, C₁₋₄ alkyl,        C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, C₂₋₄ alkenyl, C₂₋₄        alkynyl, phenyl a 5- or 6-membered or heteroaryl,        C₃₋₆cycloalkyl, —O—C₃₋₆cycloalkyl, heterocyclyl,        —(OCH₂CH₂)_(m)—OCH₃ wherein m is an integer from 1 to 6,        NR_(q)R_(r), wherein R_(q) and R_(r) are each independently        hydrogen, C₁₋₄ alkyl or R_(q) and R_(r) are linked together such        that, together with the nitrogen atom to which they are        attached, they form a 3- to 6-membered heterocyclic ring;        wherein any C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, phenyl, 5-        or 6-membered or heteroaryl, C₃₋₆cycloalkyl, —O—C₃₋₆cycloalkyl,        heterocyclyl or —O-heterocyclyl (carbon-linked) is optionally        further substituted by one or more substituents selected from        C₁₋₂alkyl, cyano, C₁₋₂haloalkyl, hydroxy, C₁₋₂ alkoxy, halo,        C₁₋₂haloalkoxy, NR_(1ea)R_(1fa) or —S(O)₀₋₂R_(1ea)R_(1fa),        wherein R_(1ea) and R_(1fa) are H or C₁₋₂alkyl.    -   (v) R₂₁, R₂₄ and R₃₀, are independently selected from hydrogen        or methyl;    -   (vi) R₂₈ and R₂₉ are selected from hydrogen or halo, methoxy and        methyl.

In an embodiment:

-   -   (i) R₄, R₅, R_(X5a), R_(X5b), R_(Y5), R_(B5N), R_(Y5N), R₆, R₇,        R₈, R₉, R₁₀, R₁₁, R_(11a), R_(11b), R_(11N), R_(Z2), R_(Z2N)        R_(Z2a), R_(Z3a), R_(Zi1b), R_(Zi2e), R_(Z9), R_(Z10), R_(Z11),        R_(Z12), R_(Z12a), R_(Z13), R_(Z14), R_(Z15) and R_(Z16) are        hydrogen;    -   (ii) R_(Z1) and R_(Z1a) are selected from hydrogen, cyano, halo,        C₁₋₂haloalkyl, C₁₋₂haloalkoxy, C₁₋₂alkoxy, C₃₋₆cycloalkyl and        —O—C₃₋₆cycloalkyl;    -   (iii) R₁₂, R₁₃, R₁₆, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, R₂₃, R₂₄ and R₃₀        are hydrogen;    -   (iv) R₁₇ is selected from hydrogen, halo, cyano, C₁₋₂ alkyl,        C₁₋₂ haloalkyl, C₁₋₂ alkoxy, C₁₋₂ haloalkoxy, C₂₋₃ alkenyl, C₂₋₃        alkynyl, phenyl a 5- or 6-membered or heteroaryl,        C₃₋₆cycloalkyl, —O—C₃₋₆cycloalkyl, heterocyclyl,        —(OCH₂CH₂)_(m)—OCH₃ wherein m is an integer from 1 to 6,        NR_(q)R_(r), wherein R_(q) and R_(r) are each independently        hydrogen, C₁₋₂ alkyl or R_(q) and R_(r) are linked together such        that, together with the nitrogen atom to which they are        attached, they form a 3- to 6-membered heterocyclic ring;        wherein any C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, phenyl, 5-        or 6-membered or heteroaryl, C₃₋₆cycloalkyl, —O—C₃₋₆cycloalkyl,        heterocyclyl or —O-heterocyclyl (carbon-linked) is optionally        further substituted by one or more substituents selected from        C₁₋₂alkyl, cyano, C₁₋₂haloalkyl, hydroxy, C₁₋₂alkoxy, halo,        C₁₋₂haloalkoxy, NR_(1ea)R_(1fa) or —S(O)₀₋₂R_(1ea)R_(1fa),        wherein R_(1ea) and Rif are H or C₁₋₂alkyl    -   (v) R₂₁, R₂₄ and R₃₀, are hydrogen;    -   (vi) R₂₈ and R₂₉ are hydrogen.

Suitably, X is as defined in any one of paragraphs (11) to (22) above.More suitably, X is as defined in paragraph (14), (15), (16) or (22).Most suitably, X is as defined in paragraph (22).

Suitably, Q₁ is as defined in any one of paragraphs (1) to (4) above.Most suitably, Q₁ is as defined in paragraph (3) or (4).

Suitably, Q_(2a) is as defined in paragraph (5).

Suitably, Q_(2b) is as defined in paragraph (6).

Suitably, Q_(2c) is as defined in paragraph (7).

Suitably, Q_(2d) is as defined in paragraph (8).

Suitably, Q₃ is as defined in paragraph (9).

Suitably, Q₄ is as defined in paragraph (10).

Suitably, R_(1a) is as defined in any one of paragraphs (23) to (42)above. Suitably, R_(1a) is as defined in any one of paragraphs (30) to(35) or (36) to (42). More suitably, R_(1a) is as defined in any one ofparagraphs (32) to (35) or (40) to (42). Most suitably, R_(1a) is asdefined in any one of paragraphs (40) to (42), e.g. paragraphs (40a),(41a), (41b), (41c) or (42).

Suitably, R_(1b) is as defined in any one of paragraphs (43) to (44).Most suitably, R_(1b) is as defined in paragraph (44).

Suitably, R_(1x) is as defined in any one of paragraphs (45) or (46).Most suitably, R_(1x) is as defined in paragraph (46).

Suitably, R_(2a), R_(2b), R₂, and R_(2d) are as defined in any one ofparagraphs (47) to (52) above. Most suitably, R_(2a), R_(2b) and R_(2c)are as defined in paragraph (51) or (52).

Suitably, Y is as defined in any one of paragraphs (63) to (89) above.Most suitably, Y is as defined in any one of paragraphs (86), (87), (88)or (89).

Suitably, n is as defined in any one of paragraphs (60) to (62) above.Most suitably, n is as defined in paragraph (62), i.e. n is 1.

Suitably, R_(3a1), R_(3b1), R_(3c1), R_(3d1), R_(3e1), R_(3f1), R_(3g1),R_(3h1), R_(3i1), R_(3j1), R_(3k1), R_(3l1), R_(3m1), R_(3n1), R_(3o1),R_(3p1), R_(3q1), R_(3r1) and R_(3s1) are as defined in any one ofparagraphs (53) to (56), and paragraphs (58) to (59) above. Mostsuitably, R_(3a1), R_(3b1), R_(3c1), R_(3d1), R_(3e1), R_(3f1), R_(3g1),R_(3h1), R_(3i1), R_(3j1), R_(3k1), R_(3l1), R_(3m1), R_(3n1), R_(3o1),R_(3p1), R_(3q1), R_(3r1) and R_(3s1) are as defined in paragraph (56)or (58).

Suitably, R_(3a2), R_(3b2), R_(3c2), R_(3d2), R_(3e2), R_(3f2), R_(3g2),R_(3h2), R_(3i2), R_(3j2), R_(3k2), R_(3l2), R_(3m2), R_(3n2), R_(3o2),R_(3p2), R_(3q2), R_(3r2) and R_(3s2) are as defined in any one ofparagraphs (57), (58) and (59) above. Most suitably, R_(3a2), R_(3b2),R_(3c2), R_(3d2), R_(3e2), R_(3f2), R_(3g2), R_(3h2), R_(3i2), R_(3j2),R_(3k2), R_(3l2), R_(3m2), R_(3n2), R_(3o2), R_(3p2), R_(3q2), R_(3r2)and R_(3s2) are as defined in paragraph (57) or (58) above.

Suitably, Z is as defined in any one of paragraphs from (136) to (193)above. More suitably, Z is as defined in paragraphs (187) to (193). Mostsuitably, Z is as defined in any one of paragraphs (190) to (193)

Suitably, R₄, R₅ and R₆ are as defined in any one of paragraphs (90) and(91). Most suitably, R₄, R₅ and R₆ are as defined in paragraph (91),i.e. R₄, R₅ and R₆ are hydrogen.

Suitably, when Z is:

then R₇, R₉ and R_(11N) are as defined in any one of paragraphs (92) and(93) above. Most suitably, R₇, R₉ and R_(11N) are as defined inparagraph (93).

Suitably, when Z is

then R₈, R₉, R₁₀ and R₁₁ are as defined in any one of paragraphs (94) to(98) above. More suitably, R₈, R₉, R₁₀ and R₁₁ are as defined in any oneof paragraphs (95) to (98) above. Most Most suitably, R₈, R₉, R₁₀ andR₁₁ are as defined in paragraph (97), (97a) or (98).

Suitably, R_(Z1) and R_(Z1a) are as defined in any one of paragraphs(99) to (102). Most suitably, R_(Z1) and R_(Z1a) are as defined inparagraph (102).

Suitably, R_(Z2), R_(Z2a), R_(Z3a), R_(Zi1b) and R_(Zi2e) are as definedin any one of paragraphs (103) to (105). Most suitably, R_(Z2), R_(Z2a),R_(Z3a), R_(Z3e), R_(Zi1b) and R_(Zi2e) are as defined in paragraph(105).

Suitably, R_(B5N), R_(Y5N), R_(Z2N) and R_(11N) are as defined inparagraph (106) or (107). Most suitably, R_(B5N), R_(Y5N), R_(Z2N) andR_(11N) are as defined in paragraph (106).

Suitably, R_(Z4), R_(Z5), R_(Z6), R_(Z7), R_(Z8), R_(Z9), R_(Z10),R_(Z11), R_(Z12), R_(Z13), R_(Z14), R_(Z15), and R_(Z16) are as definedin any one of paragraphs (108) to (110). Most suitably, R_(Z4), R_(Z5),R_(Z6), R_(Z7), R_(Z8), R_(Z9), R_(Z10), R_(Z11), R_(Z12), R_(Z13),R_(Z14), R_(Z15), and R_(Z16) are as defined in paragraph (110).

Suitably, A₁, A₂, A₅, A₆, A₇, A₈, A₉ and A₁₁ are as defined in paragraph(111)

Suitably, R₁₂, R₁₃, R₁₆, R₁₉, R₂₀, R₂₁, R₂₂ and R₂₃ are as defined inany one of paragraphs (112) or (113) above. Most suitably, R₁₂, R₁₃,R₁₆, R₁₉, R₂₀, R₂₁, R₂₂ and R₂₃ are as defined in paragraph (113).

Suitably, R₁₂ is as defined in any one of paragraphs (114) to (117)above. Most suitably, R₁₂ are as defined in paragraph (117), i.e. R₁₂ ishydrogen.

Suitably, R₁₃ is as defined in any one of paragraphs (118) to (120)above. Most suitably, R₁₃ is as defined in paragraph (119).

Suitably, R₁₆ and R₁₈ are as defined in any one of paragraphs (121) to(124) above. Most suitably, R₁₆ and R₁₈ are as defined in paragraph(124), i.e. R₁₆ and R₁₈ are hydrogen.

Suitably, R₁₇ is as defined in any one of paragraphs (125) to (131)above. More suitably, R₁₇ is as defined any one of paragraphs (128) to(131). Most suitably, R₁₇ is as defined any one of paragraphs (129) to(131).

Suitably, R₂₈ and R₂₉ are as defined in any one of paragraphs (132) to(133) above. Most suitably, R₂₈ and R₂₉ are as defined in paragraph(133).

Suitably, R₂₁, R₂₄ and R₃₀ are as defined in any one of paragraphs from(134) to (135) above. Most suitably, R₂₁, R₂₄ and R₃₀ are as defined inparagraph (135).

Suitably, R₄, R₅, R_(X5a), R_(X5b), R₆, R₇, R₈, R₉, R₁₀, R₁₁, R_(11N),R_(Z1), R_(Z1a), R_(Z2), R_(Z2a), R_(Z3a), R_(Zi1b), R_(Zi1c), R_(Zi2e),R_(Z9), R_(Z10), R_(Z11), R_(Z12), R_(Z13), R_(Z14), R_(Z15) and R_(Z16)are independently selected from hydrogen or methyl. Most suitably, R₄,R₅, R_(X5a), R_(X5b), R₆, R₇, R₈, R₉, R₁₀, R₁₁, R_(11N), R_(Z1),R_(Z1a), R_(Z2), R_(Z2a), R_(Z3a), R_(Zi1b), R_(Zi1e), R_(Zi2e), R_(Z9),R_(Z10), R_(Z11), R_(Z12), R_(Z13), R_(Z14), R_(Z15) and R_(Z16) arehydrogen.

In a particular group of compounds of the invention, Y is as defined inparagraph (63), i.e. the compounds have the structural formula (II) (asub-definition of formula (I)) shown below:

wherein X, R_(3a1), R_(3a2), n and Z each having any one of the meaningsdefined herein; or a pharmaceutically acceptable salt thereof.

In an embodiment of the compounds of formula (II):

X is as defined in any one of paragraphs (11) to (22) above;R_(3a1) is as defined in any one of paragraphs from (53) to (56), andparagraphs (58) to (59) above;R_(3a2) is as defined in any one of paragraphs (57), (58) and (59)above;n is as defined in any one of paragraphs (60) to (62) above; andZ is as defined in any one of paragraphs (136) to (193) above.

In an embodiment of the compounds of formula (II):

X is as defined in paragraph (22) above;R_(3a1) is as defined in paragraph (56) above;R_(3a2) is as defined in paragraph (57) above;n is as defined in paragraph (62) above; andZ is as defined in any one of paragraphs (136) to (193) above.

In a particular group of the compounds of formula (II):

X is as defined in paragraph (20), (21) or (22) above and R_(1a), is asdefined in any one of paragraphs (23) to (42) above;R_(3a1) is as defined in paragraph (56) above;R_(3a2) is as defined in paragraph (57) above;n is as defined in paragraph (62) above; andZ is as defined in any one of paragraphs (136) to (193) above.

In a particular group of the compounds of formula (II):

X is as defined in paragraph (22) above and R_(1a) is as defined in anyone of paragraphs (36) to (42) above;R_(3a1) is as defined in paragraph (56) above;R_(3a2) is as defined in paragraph (57) above;n is as defined in paragraph (62) above; andZ is as defined in any one of paragraphs (136) to (193) above.

In a particular group of the compounds of formula (II):

X is as defined in paragraph (22) above and R_(1a) is as defined inparagraph (32) or (35) above;R_(3a1) is as defined in paragraph (56) above;R_(3a2) is as defined in paragraph (57) above;n is as defined in paragraph (62) above; andZ is as defined in any one of paragraphs (136) to (193) above.

In an embodiment of the compounds of formula (II):

X is as defined in paragraph (14) above;R_(3a1) is as defined in any one of paragraphs from (53) to (56), andparagraphs (58) to (59) above;R_(3a2) is as defined in any one of paragraphs (57), (58) and (59)above;n is as defined in any one of paragraphs (60) to (62) above; andZ is as defined in any one of paragraphs (142), (146) and (156) above.

In a particular group of compounds of the invention, Y is as defined inparagraph (73), i.e. the compounds have the structural formula (II) (asub-definition of formula (I)) shown below:

wherein X, R_(3i1), R_(3i2), n and Z each having any one of the meaningsdefined herein; or a pharmaceutically acceptable salt thereof.

In an embodiment of the compounds of formula (III):

X is as defined in any one of paragraphs (11) to (22) above;R_(3i1) is as defined in any one of paragraphs from (53) to (56), andparagraphs (58) to (59) above;R_(3i2) is as defined in any one of paragraphs (57), (58) and (59)above;n is as defined in any one of paragraphs (60) to (62) above; andZ is as defined in any one of paragraphs (136) to (193) above.

In an embodiment of the compounds of formula (III):

X is as defined in paragraph (22) above;R_(3i1) is as defined in paragraph (56) above;R_(3i2) is as defined in paragraph (57) above;n is as defined in paragraph (62) above; andZ is as defined in any one of paragraphs (136) to (193) above.

In a particular group of the compounds of formula (III):

X is as defined in paragraph (20), (21) or (22) above and R_(1a), is asdefined in any one of paragraphs (23) to (42) above;R_(3i1) is as defined in paragraph (56) above;R_(3i2) is as defined in paragraph (57) above;n is as defined in paragraph (62) above; andZ is as defined in any one of paragraphs (136) to (193) above.

In a particular group of the compounds of formula (III):

X is as defined in paragraph (22) above and R₁, is as defined in any oneof paragraphs (30) to (35) or (36) to (42) above;R_(3i1) is as defined in paragraph (56) above;R_(3i2) is as defined in paragraph (57) above;n is as defined in paragraph (62) above; andZ is as defined in any one of paragraphs (136) to (193) above.

In a particular group of compounds of the invention, Y is as defined inparagraph (64), i.e. the compounds have the structural formula (IV) (asub-definition of formula (I)) shown below:

wherein X, n and Z each having any one of the meanings defined herein;or a pharmaceutically acceptable salt thereof.

In an embodiment of the compounds of formula (IV):

X is as defined in any one of paragraphs (11) to (22) above;n is as defined in any one of paragraphs (60) to (62) above; andZ is as defined in any one of paragraphs (136) to (193) above.

In an embodiment of the compounds of formula (IV):

X is as defined in paragraph (22) above;n is as defined in paragraph (62) above; andZ is as defined in any one of paragraphs (136) to (193) above.

In a particular group of the compounds of formula (IV):

X is as defined in paragraph (20), (21) or (22) above and R_(1a), is asdefined in any one of paragraphs (23) to (42) above;n is as defined in paragraph (62) above; andZ is as defined in any one of paragraphs (136) to (193) above.

In a particular group of the compounds of formula (IV):

X is as defined in paragraph (22) above and R_(1a) is as defined in anyone of paragraphs (30) to (35) or (36) to (42) above;n is as defined in paragraph (62) above; andZ is as defined in any one of paragraphs (136) to (193) above.

In a particular group of compounds of the invention, Y is as defined inparagraph (74), i.e. the compounds have the structural formula (V) (asub-definition of formula (I)) shown below:

wherein X, R_(3j1), R_(3j2), n and Z each having any one of the meaningsdefined herein; or a pharmaceutically acceptable salt thereof.

In an embodiment of the compounds of formula (V):

X is as defined in any one of paragraphs (11) to (22) above;R_(3j1) is as defined in any one of paragraphs from (53) to (56), andparagraphs (58) to (59) above;R_(3j2) is as defined in any one of paragraphs (57), (58) and (59)above;n is as defined in any one of paragraphs (60) to (62) above; andZ is as defined in any one of paragraphs (136) to (193) above.

In an embodiment of the compounds of formula (V):

X is as defined in paragraph (22) above;R_(3j1) is as defined in paragraph (56) above;R_(3j2) is as defined in paragraph (57) above;n is as defined in paragraph (62) above; andZ is as defined in any one of paragraphs (136) to (193) above.

In a particular group of the compounds of formula (V):

X is as defined in paragraph (20), (21) or (22) above and R_(1a), is asdefined in any one of paragraphs (23) to (42) above;R_(3j1) is as defined in paragraph (56) above;R_(3j2) is as defined in paragraph (57) above;n is as defined in paragraph (62) above; andZ is as defined in any one of paragraphs (136) to (193) above.

In a particular group of the compounds of formula (V):

X is as defined in paragraph (22) above and R_(1a) is as defined in anyone of paragraphs (30) to (35) or (36) to (42) above;R_(3j1) is as defined in paragraph (56) above;R_(3j2) is as defined in paragraph (57) above;n is as defined in paragraph (62) above; andZ is as defined in any one of paragraphs (136) to (193) above.

In a particular group of compounds of the invention, X is as defined inparagraph (15), i.e. the compounds have the structural formula (VI) (asub-definition of formula (I)) shown below:

wherein R_(1a), R_(1b), R_(2a), R_(2b), R_(2d), Y and Z each having anyone of the meanings defined herein; or a pharmaceutically acceptablesalt thereof.

In an embodiment of the compounds of formula (VI):

Q₁ is as defined in any one of paragraphs (1) to (4)R_(1a) is as defined in any one of paragraphs (23) to (42) above;R_(1b) is as defined in any one of paragraphs (43) to (44) above;R_(2a), R_(2b) and R_(2d) are as defined in any one of paragraphs (47)to (52) above;Y is as defined in any one of paragraphs (63) to (89) above; andZ is as defined in any one of paragraphs (136) to (193) above.

In an embodiment of the compounds of formula (VI):

Q₁ is as defined in any one of paragraphs (3) or (4);R_(1a) is as defined in any one of paragraphs (30) to (35) above;R_(1b) is as defined in paragraph (44) above;R_(2a), R_(2b), and R_(2d) are as defined in paragraph (51) or (52);Y is as defined in paragraphs (86), (87), (88) or (89) above; andZ is as defined in any one of paragraphs (186) to (193) above.

In an embodiment of the compounds of formula (VI):

Q₁ is as defined in any one of paragraphs (3) or (4);R_(1a) is as defined in any one of paragraphs (38) to (42) above;R_(1b) is as defined in paragraph (44) above;R_(2a), R_(2b), and R_(2d) are as defined in paragraph (51) or (52);Y is as defined in paragraphs (86), (87), (88) or (89) above; andZ is as defined in any one of paragraphs (136) to (193) above.

In an embodiment of the compounds of formula (VI):

Q₁ is as defined in paragraph (3) or (4)R_(1a) is as defined in any one of paragraphs (38) to (42) above;R_(1b) is as defined in paragraph (44) above;R_(2a), R_(2b), and R_(2d) are as defined in paragraph (51) or (52);Y is as defined in any one of paragraphs (85) to (89) above; andZ is as defined in any one of paragraphs (189) to (193) above.

In a particular group of the compounds of formula (VI):

Q₁ is as defined in paragraph (4)R_(1a) is as defined in paragraph (32) or (35) above;R_(1b) is as defined in paragraph (44) above;R_(2a), R_(2b), and R_(2d) are as defined in paragraph (52);Y is as defined in paragraph (89) above;Z is as defined in any one of paragraph (193) above.

In a particular group of the compounds of formula (XI):

Q₁ is as defined in paragraph (4)R_(1a) is as defined in any one of paragraphs (40a), (41a), (41b), (41c)or (42) above;R_(1b) is as defined in paragraph (44) above;R_(2a), R_(2b), and R_(2d) are as defined in paragraph (52);Y is as defined in paragraph (89) above; andZ is as defined in paragraph (193) above.

In a particular group of compounds of the invention, X is as defined inparagraph (15) and Y is as defined in paragraph (63), i.e. the compoundshave the structural formula (VII) (a sub-definition of formula (I))shown below:

wherein R_(1a), R_(1b), R_(2a), R_(2b), R_(2d), R_(3a1), R_(3a2), n andZ each having any one of the meanings defined herein; or apharmaceutically acceptable salt thereof.

In an embodiment of the compounds of formula (VII):

Q₁ is as defined in any one of paragraphs (1) to (4)R_(1a) is as defined in any one of paragraphs (23) to (42) above;R_(1b) is as defined in any one of paragraphs (43) to (44) above;R_(2a), R_(2b) and R_(2d) are as defined in any one of paragraphs (47)to (52) above;R_(3a1) is as defined in any one of paragraphs from (53) to (56), andparagraphs (58) to (59) above;R_(3a2) is as defined in any one of paragraphs (57), (58) and (59)above;n is as defined in any one of paragraphs (60), (61) and (62) above;Z is as defined in any one of paragraphs (136) to (193) above.

In an embodiment of the compounds of formula (VII):

Q₁ is as defined in any one of paragraphs (3) or (4);R_(1a) is as defined in any one of paragraphs (30) to (35) above;R_(1b) is as defined in paragraph (44) above;R_(2a), R_(2b), and R_(2d) are as defined in paragraph (51) or (52);R_(3a1) is as defined in paragraph (56) above;R_(3a2) is as defined in paragraph (57) above;n is as defined in paragraph (62) above; andZ is as defined in any one of paragraphs (186) to (191) above.

In an embodiment of the compounds of formula (VII):

Q₁ is as defined in any one of paragraphs (3) or (4);R_(1a) is as defined in any one of paragraphs (38) to (42) above;R_(1b) is as defined in paragraph (44) above;R_(2a), R_(2b), and R_(2d) are as defined in paragraph (51) or (52);R_(3a1) is as defined in paragraph (56) above;R_(3a2) is as defined in paragraph (57) above;n is as defined in paragraph (62) above; andZ is as defined in any one of paragraphs (136) to (193) above.

In an embodiment of the compounds of formula (VII):

Q₁ is as defined in any one of paragraphs (3) or (4);R_(1a) is as defined in any one of paragraphs (38) to (42) above;R_(1b) is as defined in paragraph (44) above;R_(2a), R_(2b), and R_(2d) are as defined in paragraph (51) or (52);R_(3a1) is as defined in paragraph (56) above;R_(3a2) is as defined in paragraph (57) above;n is as defined in paragraph (62) above; andZ is as defined in any one of paragraphs (186) to (191) above.

In an embodiment of the compounds of formula (VII):

Q₁ is as defined in any one of paragraphs (3) or (4);R_(1a) is as defined in paragraph (32) or (35) above;R_(1b) is as defined in paragraph (44) above;R_(2a), R_(2b), and R_(2d) are as defined in paragraph (51) or (52);R_(3a1) is as defined in paragraph (56) above;R_(3a2) is as defined in paragraph (57) above;n is as defined in paragraph (62) above; andZ is as defined in any one of paragraphs (186) to (191) above.

In an embodiment of the compounds of formula (VII):

Q₁ is as defined in any one of paragraphs (3) or (4);R_(1a) is as defined in any one of paragraphs (38) to (42) above;R_(1b) is as defined in paragraph (44) above;R_(2a), R_(2b), and R_(2d) are as defined in paragraph (51) or (52);R_(3a1) is as defined in paragraph (56) above;R_(3a2) is as defined in paragraph (57) above;n is as defined in paragraph (62) above; andZ is as defined in paragraph (193) above.

In a particular group of compounds of the invention, X is as defined inparagraph (15) and Z is defined as paragraph (146), i.e. the compoundshave the structural formula (VIII) (a sub-definition of formula (I))shown below:

wherein X, R_(1a), R_(1b), R_(2a), R_(2b), R_(2a), Y, A₅, A₆, R_(Z1) andR_(Z2) each have any one of the meanings defined herein; or apharmaceutically acceptable salt thereof.

In an embodiment of the compounds of formula (VIII):

Q₁ is as defined in any one of paragraphs (1) to (4)R_(1a) is as defined in any one of paragraphs (23) to (42) above;R_(1b) is as defined in any one of paragraphs (43) to (44) above;R_(2a), R_(2b) and R_(2d) are as defined in any one of paragraphs (47)to (52) above;Y is as defined in any one of paragraphs (63) to (89) above;R_(Z1) is as defined in any one of paragraphs from (99) to (102) above;R_(Z2) is as defined in any one of paragraphs from (103) to (105) above;A₅ is CR₁₆ and R₁₆ is as defined in any one of paragraphs (121) to (124)above; andA₆ is CR₁₇ and R₁₇ is as defined in any one of paragraphs from (125) to(131) above.

In an embodiment of the compounds of formula (VIII):

Q₁ is as defined in paragraph (3) or (4)R_(1a) is as defined in any one of paragraphs (30) to (35) above;R_(1b) is as defined in paragraph (44) above;R_(2a), R_(2b), and R_(2d) are as defined in paragraph (51) or (52);Y is as defined in any one of paragraphs (85) to (89) above; andR_(Z1) is as defined in any one of paragraphs from (101) to (102) above;R_(Z2) is as defined in any one of paragraphs from (104) to (105) above;A₅ is CR₁₆ and R₁₆ is as defined in any one of paragraphs (123) to (124)above; andA₆ is CR₁₇ and R₁₇ as defined in any one of paragraphs from (128) to(131) above.

In an embodiment of the compounds of formula (VIII):

Q₁ is as defined in paragraph (3) or (4)R_(1a) is as defined in any one of paragraphs (38) to (42) above;R_(1b) is as defined in paragraph (44) above;R_(2a), R_(2b), and R_(2d) are as defined in paragraph (51) or (52);Y is as defined in any one of paragraphs (85) to (89) above; andR_(Z1) is as defined in any one of paragraphs from (101) to (102) above;R_(Z2) is as defined in any one of paragraphs from (104) to (105) above;A₅ is CR₁₆ and R₁₆ is as defined in any one of paragraphs (123) to (124)above; andA₆ is CR₁₇ and R₁₇ as defined in any one of paragraphs from (128) to(131) above.

In a particular group of the compounds of formula (VIII):

Q₁ is as defined in paragraph (4)R_(1a) is as defined in any one of paragraphs (40a), (41a), (41b), (41c)or (42) above;R_(1b) is as defined in paragraph (44) above;R_(2a), R_(2b), and R_(2d) are as defined in paragraph (52);Y is as defined in any one of paragraphs (87), (88) or (89) above;R_(Z1) is as defined in any one of paragraphs (102) above;R_(Z2) is as defined in paragraph (105) above;A₅ is CR₁₆ and R₁₆ is as defined in paragraph (124) above; andA₆ is CR₁₇ and R₁₇ as defined in any one of paragraphs from (130) to(131) above.

In a particular group of the compounds of formula (VIII):

Q₁ is as defined in paragraph (4)R_(1a) is as defined in paragraph (32) or (35) above;R_(1b) is as defined in paragraph (44) above;R_(2a), R_(2b), and R_(2d) are as defined in paragraph (52);Y is as defined in any one of paragraphs (87), (88) or (89) above;R_(Z1) is as defined in any one of paragraphs (102) above;R_(Z2) is as defined in paragraph (105) above;A₅ is CR₁₆ and R₁₆ is as defined in paragraph (124) above; andA₆ is CR₁₇ and R₁₇ as defined in any one of paragraphs from (130) to(131) above.

In a particular group of compounds of the invention, X is as defined inparagraph (14), (15) or (16) and Z is defined as paragraph (142), i.e.the compounds have the structural formula (IX) or (X) (a sub-definitionof formula (I)) shown below:

wherein R_(1a), R_(1b), R_(2a), R_(2b), R_(2d), Q₁, Y, A₁, A₂, R₄, R₅and R₆ each having any one of the meanings defined herein; or apharmaceutically acceptable salt thereof.

In an embodiment of the compounds of formula (IX):

Q₁ is as defined in any one of paragraphs (1) to (4)R_(1a) is as defined in any one of paragraphs (23) to (42) above;R_(1b) is as defined in any one of paragraphs (43) to (44) above;R_(2a), R_(2b) and R_(2d) are as defined in any one of paragraphs (47)to (52) above;Y is as defined in any one of paragraphs (63) to (89) above;A₁ is CR₁₂, and R₁₂ is as defined in any one of paragraphs (112), (113),or (114) to (117) above;A₂ is CR₁₃ and R₁₃ is as defined in any one of paragraphs (112), (113),or (118) to (120) above;R₄ is as defined in paragraph (90) or (91) above;R₅ is as defined in paragraph (90) or (91) above; andR₆ is as defined in paragraph (90) or (91) above.

In an embodiment of the compounds of formula (IX):

Q₁ is as defined in paragraph (3) or (4)R_(1a) is as defined in any one of paragraphs (30) to (35) above;R_(1b) is as defined in paragraph (44) above;R_(2a), R_(2b), and R_(2d) are as defined in paragraph (51) or (52);Y is as defined in any one of paragraphs (85) to (89) above;A₁ is CR₁₂, and R₁₂ is as defined in any one of paragraphs (114) to(117) above;A₂ is CR₁₃ and R₁₃ is as defined in paragraph (120) above;R₄ is as defined in paragraph (91) above;R₅ is as defined in paragraph (91) above; andR₆ is as defined in paragraph (91) above.

In an embodiment of the compounds of formula (IX):

Q₁ is as defined in paragraph (3) or (4)R_(1a) is as defined in any one of paragraphs (38) to (42) above;R_(1b) is as defined in paragraph (44) above;R_(2a), R_(2b), and R_(2d) are as defined in paragraph (51) or (52);Y is as defined in any one of paragraphs (85) to (89) above;A₁ is CR₁₂, and R₁₂ is as defined in any one of paragraphs (114) to(117) above;A₂ is CR₁₃ and R₁₃ is as defined in paragraph (120) above;R₄ is as defined in paragraph (91) above;R₅ is as defined in paragraph (91) above; andR₆ is as defined in paragraph (91) above.

In an embodiment of the compounds of formula (IX):

Q₁ is as defined in paragraph (4)R_(1a) is as defined in any one of paragraphs (40a), (41a), (41b), (41c)or (42) above;R_(1b) is as defined in paragraph (44) above;R_(2a), R_(2b), and R_(2d) are as defined in paragraph (52);Y is as defined in any one of paragraphs (88) or (89) above;A₁ is CR₁₂, and R₁₂ is as defined in any one of paragraphs (116) to(117) above;A₂ is CR₁₃ and R₁₃ is as defined in paragraph (120) above;R₄ is as defined in paragraph (91) above;R₅ is as defined in paragraph (91) above; andR₆ is as defined in paragraph (91) above.

In an embodiment of the compounds of formula (IX):

Q₁ is as defined in paragraph (4)R_(1a) is as defined in paragraph (32) or (35) above;R_(1b) is as defined in paragraph (44) above;R_(2a) and R_(2d) are as defined in paragraph (52);Y is as defined in any one of paragraphs (88) or (89) above;A₁ is CR₁₂, and R₁₂ is as defined in any one of paragraphs (116) to(117) above;A₂ is CR₁₃ and R₁₃ is as defined in paragraph (120) above;R₄ is as defined in paragraph (91) above;R₅ is as defined in paragraph (91) above; andR₆ is as defined in paragraph (91) above.

In an embodiment of the compounds of formula (X):

Q₁ is as defined in any one of paragraphs (1) to (4)R_(1a) is as defined in any one of paragraphs (23) to (42) above;R_(1b) is as defined in any one of paragraphs (43) to (44) above;R_(2a) and R_(2d) are as defined in any one of paragraphs (47) to (52)above;Y is as defined in any one of paragraphs (63) to (89) above;A₁ is CR₁₂, and R₁₂ is as defined in any one of paragraphs (112), (113),or (114) to (117) above:A₂ is CR₁₃ and R₁₃ is as defined in any one of paragraphs (112), (113)or (118) to (120) above;R₄ is as defined in paragraph (90) or (91) above;R₅ is as defined in paragraph (90) or (91) above; andR₆ is as defined in paragraph (90) or (91) above.

In an embodiment of the compounds of formula (X):

Q₁ is as defined in paragraph (3) or (4)R_(1a) is as defined in any one of paragraphs (38) to (42) above;R_(1b) is as defined in paragraph (44) above;R_(2a) and R_(2d) are as defined in paragraph (51) or (52);Y is as defined in any one of paragraphs (85) to (89) above;A₁ is CR₁₂, and R₁₂ is as defined in any one of paragraphs (114) to(117) above;A₂ is CR₁₃ and R₁₃ is as defined in paragraph (120) above;R₄ is as defined in paragraph (91) above;R₅ is as defined in paragraph (91) above; andR₆ is as defined in paragraph (91) above.

In an embodiment of the compounds of formula (X):

Q₁ is as defined in paragraph (4)R_(1a) is as defined in any one of paragraphs (40a), (41a), (41b), (41c)or (42) above;R_(1b) is as defined in paragraph (44) above;R_(2a) and R_(2d) are as defined in paragraph (52);Y is as defined in any one of paragraphs (88) or (89) above;A₁ is CR₁₂, and R₁₂ is as defined in any one of paragraphs (116) to(117) above;A₂ is CR₁₃ and R₁₃ is as defined in paragraph (120) above;R₄ is as defined in paragraph (91) above;R₅ is as defined in paragraph (91) above; andR₆ is as defined in paragraph (91) above.

In an embodiment of the compounds of formula (X):

Q₁ is as defined in paragraph (4)R_(1a) is as defined in paragraph (32) or (35) above;R_(1b) is as defined in paragraph (44) above;R_(2a), R_(2b), and R_(2d) are as defined in paragraph (52);Y is as defined in any one of paragraphs (88) or (89) above;A₁ is CR₁₂, and R₁₂ is as defined in any one of paragraphs (116) to(117) above;A₂ is CR₁₃ and R₁₃ is as defined in paragraph (120) above;R₄ is as defined in paragraph (91) above;R₅ is as defined in paragraph (91) above; andR₆ is as defined in paragraph (91) above.

In a particular group of compounds of the invention, X is as defined inparagraph (15) and Z is defined as paragraph (147), i.e. the compoundshave the structural formula (XI) (a sub-definition of formula (I)) shownbelow:

wherein X, R_(1a), R_(1b), R_(2a), R_(2b), R_(2d), Y, A₅, A₆, R_(Z1),R_(Z2) and R_(Zi1b) each have any one of the meanings defined herein; ora pharmaceutically acceptable salt thereof.

In an embodiment of the compounds of formula (XI):

Q₁ is as defined in any one of paragraphs (1) to (4)R_(1a) is as defined in any one of paragraphs (23) to (42) above;R_(1b) is as defined in any one of paragraphs (43) to (44) above;R_(2a), R_(2b) and R_(2d) are as defined in any one of paragraphs (47)to (52) above;Y is as defined in any one of paragraphs (63) to (89) above; andA₅ is CR₁₆ and R₁₆ is as defined in any one of paragraphs (121) to (124)above;A₆ is CR₁₇ and R₁₇ is as defined in any one of paragraphs from (125) to(131) above;R_(Z1) is as defined in any one of paragraphs from (99) to (102) above;R_(Z2) is as defined in any one of paragraphs from (103) to (105) above;andR_(Zi1b) is as defined in any one of paragraphs from (103) to (105)above;

In an embodiment of the compounds of formula (XI):

Q₁ is as defined in paragraph (3) or (4)R_(1a) is as defined in any one of paragraphs (38) to (42) above;R_(1b) is as defined in paragraph (44) above;R_(2a), R_(2b), and R_(2d) are as defined in paragraph (51) or (52);Y is as defined in any one of paragraphs (85) to (89) above; andA₅ is CR₁₆ and R₁₆ is as defined in any one of paragraphs (123) to (124)above;A₆ is CR₁₇ and R₁₇ as defined in any one of paragraphs from (128) to(131) above;R_(Z1) is as defined in any one of paragraphs from (101) to (102) above;R_(Z2) is as defined in any one of paragraphs from (104) to (105) above;andR_(Zi1b) is as defined in any one of paragraphs from (104) to (105)above.

In an embodiment of the compounds of formula (XI):

Q₁ is as defined in paragraph (3) or (4)R_(1a) is as defined in any one of paragraphs (30) to (35) above;R_(1b) is as defined in paragraph (44) above;R_(2a), R_(2b), and R_(2d) are as defined in paragraph (51) or (52);Y is as defined in any one of paragraphs (85) to (89) above; andA₅ is CR₁₆ and R₁₆ is as defined in any one of paragraphs (123) to (124)above;A₆ is CR₁₇ and R₁₇ as defined in any one of paragraphs from (128) to(131) above;R_(Z1) is as defined in any one of paragraphs from (101) to (102) above;R_(Zn) is as defined in any one of paragraphs from (104) to (105) above;andR_(Zi1b) is as defined in any one of paragraphs from (104) to (105)above.

In a particular group of the compounds of formula (XI):

Q₁ is as defined in paragraph (4)R_(1a) is as defined in any one of paragraphs (40a), (41a), (41b), (41c)or (42) above;R_(1b) is as defined in paragraph (44) above;R₂₁, R_(2b), and R_(2d) are as defined in paragraph (52);Y is as defined in any one of paragraphs (87), (88) or (89) above;A₅ is CR₁₆ and R₁₆ is as defined in paragraph (124) above;A₆ is CR₁₇ and R₁₇ as defined in any one of paragraphs from (130) to(131) above; andR_(Z1) is as defined in paragraph (102) above;R_(Z2) is as defined in paragraph (105) above; andR_(Zi1b) is as defined in paragraph (105) above.

In a particular group of the compounds of formula (XI):

Q₁ is as defined in paragraph (4)R_(1a) is as defined in paragraph (32) or (35) above;R_(1b) is as defined in paragraph (44) above;R_(2a), R_(2b), and R_(2d) are as defined in paragraph (52);Y is as defined in any one of paragraphs (87), (88) or (89) above;A₅ is CR₁₆ and R₁₆ is as defined in paragraph (124) above;A₆ is CR₁₇ and R₁₇ as defined in any one of paragraphs from (130) to(131) above; andR_(Z1) is as defined in paragraph (102) above;R_(Z2) is as defined in paragraph (105) above; andR_(Zi1b) is as defined in paragraph (105) above.

In a particular group of compounds of the invention, X is as defined inparagraph (16), i.e. the compounds have the structural formula (XII) (asub-definition of formula (I)) shown below:

wherein X, R_(1a), R_(1b), R_(2a), R_(2d), Y and Z each have any one ofthe meanings defined herein; or a pharmaceutically acceptable saltthereof.

In an embodiment of the compounds of formula (XII):

Q₁ is as defined in any one of paragraphs (1) to (4);R_(1a) is as defined in any one of paragraphs (23) to (42) above;R_(1b) is as defined in any one of paragraphs (43) to (44) above;R_(2a) and R_(2d) are as defined in any one of paragraphs (47) to (52)above;Y is as defined in any one of paragraphs (63) to (89) above; andZ is as defined in any one of paragraphs (136) to (193) above.

In an embodiment of the compounds of formula (XII):

Q₁ is as defined in paragraph (3) or (4)R_(1a) is as defined in any one of paragraphs (30) to (35) above;R_(1b) is as defined in paragraph (44) above;R_(2a) and R_(2d) are as defined in paragraph (51) or (52);Y is as defined in any one of paragraphs (85) to (89) above; andZ is as defined in any one of paragraphs (189) to (193) above.

In an embodiment of the compounds of formula (XII):

Q₁ is as defined in paragraph (3) or (4)R_(1a) is as defined in any one of paragraphs (38) to (42) above;R_(1b) is as defined in paragraph (44) above;R_(2a) and R_(2d) are as defined in paragraph (51) or (52);Y is as defined in any one of paragraphs (85) to (89) above; andZ is as defined in any one of paragraphs (189) to (193) above.

In a particular group of the compounds of formula (XII):

Q₁ is as defined in paragraph (4)R_(1a) is as defined in paragraph (32) or (35) above;R_(1b) is as defined in paragraph (44) above;R_(2a) and R_(2d) are as defined in paragraph (52);Y is as defined in paragraph (89) above;Z is as defined in any one of paragraph (193) above.

In a particular group of the compounds of formula (XII):

Q₁ is as defined in paragraph (4)R_(1a) is as defined in any one of paragraphs (40a), (41a), (41b), (41c)or (42) above;R_(1b) is as defined in paragraph (44) above;R_(2a) and R_(2d) are as defined in paragraph (52);Y is as defined in paragraph (89) above; andZ is as defined in paragraph (193) above.

In a particular group of compounds of the invention, Z is as defined inparagraph (155), i.e. the compounds have the structural formula (XIII)(a sub-definition of formula (I)) shown below:

In an embodiment of the compounds of formula (XII):

X is as defined in any one of paragraphs (11) to (22) above;Y is as defined in any one of paragraphs (63) to (89) above; andR₈, R₉, R₁₀ and R₁₁ are as defined in any one of paragraphs (94) to (98)above.

In an embodiment of the compounds of formula (XIII):

X is as defined in paragraph (14), (15), (16) or (22) above;Y is as defined in any one of paragraphs (85) to (89) above;R₈, R₉, R₁₀ and R₁₁ are as defined in any one of paragraphs (94) to (98)above.

In an embodiment of the compounds of formula (XIII):

X is as defined in paragraph (14), (15), (16) or (22) above;Y is as defined in any one of paragraphs (86), (87), (88) or (89);R₈, R₉, R₁₀ and R₁₁ are as defined in any one of paragraphs (95a) to(97) above.

In a particular group of the compounds of formula (XIII):

X is as defined in paragraph (14), (15), (16) or (22) above;Y is as defined in any one of paragraphs (88) or (89);

In a particular group of the compounds of formula (XIII):

X is as defined in paragraph (22) above;Y is as defined in paragraph (89);R₈, R₉, R₁₀ and R₁₁ are as defined in paragraph (96), (97) or (97a).

Particular compounds of the present invention include any of thecompounds exemplified in the present application, or a pharmaceuticallyacceptable salt thereof, and, in particular, any of the following:

-   N-({2-[(4,4-dimethylpiperidin-1-yl)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[(2-{[(cyclobutylmethyl)amino]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[[2-[[(3,3-difluorocyclobutyl)methylamino]methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[[2-[[(1-hydroxycyclobutyl)methylamino]methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[[2-[[(1-fluorocyclobutyl)methylamino]methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[[2-[[(1-methylcyclopropyl)methylamino]methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide.-   N-[[2-(2-azabicyclo[2.1.1]hexan-2-ylmethyl)-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[[2-(3-azabicyclo[3.1.1]heptanean-3-ylmethyl)-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[[2-[[2-(hydroxymethyl)pyrrolidin-1-yl]methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[[2-(morpholinomethyl)-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[[2-[(1-adamantylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide-   4-oxo-N-[[2-(1-piperidylmethyl)-1H-indol-6-yl]methyl]pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[[2-[(4-fluoro-1-piperidyl)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide-   4-oxo-N-[[2-[[[rac-(1S,2S,4S)-7-oxabicyclo[2.2.1]heptane-5-en-2-yl]methylamino]methyl]-1H-indol-6-yl]methyl]pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[[2-[[(1-hydroxycyclopentyl)methylamino]methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide-   4-oxo-N-[[2-[[[rac-(1S,2R,4S)-7-oxabicyclo[2.2.1]heptane-5-en-2-yl]methylamino]methyl]-1H-indol-6-yl]methyl]pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[[2-[(1-bicyclo[1.1.1]pentanylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[[2-[(cyclobutylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-({2-[({bicyclo[2.2.1]heptanean-2-yl}amino)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[[2-[(cyclopropylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[[2-(2-azabicyclo[2.2.2]octan-2-ylmethyl)-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[[2-[[(2,2-difluorocyclopropyl)methylamino]methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[(2-{[({3-fluorobicyclo[1.1.1]pentan-1-yl}methyl)amino]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[[2-[(cyclohexylmethylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[[2-[[(1-hydroxycyclohexyl)methylamino]methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[[2-[(cyclopentylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[[2-[(cyclopentylmethylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[[2-[[(1-methoxycyclobutyl)methylamino]methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[[2-[(isobutylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[[2-[(cyclohexylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[[2-[(cyclopropylmethylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide-   4-oxo-N-[[2-[(prop-2-ynylamino)methyl]-1H-indol-6-yl]methyl]pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[[2-[(oxetan-2-ylmethylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[[2-[(2,2-dimethylpropylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[[2-[(1-bicyclo[1.1.1]pentanylmethylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-{[2-({[(1S,2S)-2-hydroxycyclopentyl]amino}methyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-{[2-({[(1R,2R)-2-hydroxycyclopentyl]amino}methyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-{[2-({[(1S,2R)-2-hydroxycyclopentyl]amino}methyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-{[2-({[(1R,2S)-2-hydroxycyclopentyl]amino}methyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[[2-[(cyclopropylmethylamino)methyl]-5-fluoro-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[[2-[(cyclobutylmethylamino)methyl]-5-fluoro-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide-   4-oxo-N-[[2-[(2,2,2-trifluoroethylamino)methyl]-1H-indol-6-yl]methyl]pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[(2-{[N-(cyclobutylmethyl)acetamido]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   4-oxo-N-{[2-(piperidin-2-yl)-1H-indol-6-yl]methy}-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[(2-{[(cyclobutylmethyl)amino]methyl}-3-fluoro-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[(2-{[(cyclobutylmethyl)amino]methyl}-1-methyl-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[[2-[(Cyclobutylmethylamino)-dideuterio-methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[[2-[(cyclobutylmethylamino)methyl]-1H-indol-6-yl]methyl]-1H-indazole-4-carboxamide-   N-[[2-[(cyclobutylmethylamino)methyl]-1H-pyrrolo[3,2-b]pyridin-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-(1H-indol-6-ylmethyl)-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-(1H-indol-2-ylmethyl)-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-(indolizin-2-ylmethyl)-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[(6-{[4-(1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl]methyl}-1H-indol-2-yl)methyl]cyclopropanamine-   (1R,2S)-2-[[6-[[4-(1H-indazol-4-yl)triazol-1-yl]methyl]-1H-indol-2-yl]methylamino]cyclopentanol-   N-[[6-[[4-(1H-indazol-4-yl)triazol-1-yl]methyl]-1H-indol-2-yl]methyl]cyclopentanamine-   N-(cyclopropylmethyl)-1-[6-[[4-(1H-indazol-4-yl)triazol-1-yl]methyl]-1H-indol-2-yl]methanamine-   1-[[[6-[[4-(1H-indazol-4-yl)triazol-1-yl]methyl]-1H-indol-2-yl]methylamino]methyl]cyclobutanol-   N-(cyclobutylmethyl)-1-[6-[[4-(1H-indazol-4-yl)triazol-1-yl]methyl]-1H-indol-2-yl]methanamine-   N-(cyclobutylmethyl)-1-[6-[[4-(1H-indazol-4-yl)triazol-1-yl]methyl]-1H-pyrrolo[3,2-b]pyridin-2-yl]methanamine-   N-(cyclobutylmethyl)-1-[6-[[4-(1H-indazol-4-yl)triazol-1-yl]methyl]-1H-pyrrolo[3,2-c]pyridin-2-yl]methanamine-   N-(cyclobutylmethyl)-1-[6-[[4-(1H-indazol-4-yl)triazol-1-yl]methyl]-1H-pyrrolo[3,2-c]pyridin-2-yl]methanamine-   2-[1-[[2-[(cyclobutylmethylamino)methyl]-1H-indol-6-yl]methyl]triazol-4-yl]pyrido[1,2-a]pyrimidin-4-one-   N-(cyclobutylmethyl)-1-[6-[[4-(6-methoxyimidazo[1,5-a]pyridin-8-yl)triazol-1-yl]methyl]-1H-indol-2-yl]methanamine-   N-(cyclobutylmethyl)-1-[6-[[4-(1H-indazol-4-yl)imidazol-1-yl]methyl]-1H-indol-2-yl]methanamine-   N-(cyclobutylmethyl)-1-[6-[[3-(1H-indazol-4-yl)-1,2,4-oxadiazol-5-yl]methyl]-1H-indol-2-yl]methanamine-   N-[[2-(2-azaspiro[3.3]heptanean-2-ylmethyl)-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[[2-[(benzylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[[2-(3-azabicyclo[3.1.0]hexan-3-ylmethyl)-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[[2-[[cyclobutylmethyl(methyl)amino]methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[[2-[(cyclobutylmethylamino)methyl]-1H-pyrrolo[2,3-b]pyridin-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[(2-{[(cyclobutylmethyl)amino]methyl}-1H-1,3-benzodiazol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[(2-{[(but-2-yn-1-yl)amino]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[(2-{[(3-cyclopropylprop-2-yn-1-yl)amino]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-({2-[({bicyclo[3.1.0]hexan-6-yl}amino)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[(2-{[({bicyclo[2.1.1]hexan-1-yl}methyl)amino]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[(2-{[({3-methylbicyclo[1.1.1]pentan-1-yl}methyl)amino]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-({2-[(3-methylazetidin-1-yl)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-({2-[(3-fluoroazetidin-1-yl)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-({2-[(azetidin-1-yl)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-{[2-({2-azaspiro[3.4]octan-2-yl}methyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-({2-[(3-hydroxyazetidin-1-yl)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-({2-[(3,3-dimethylazetidin-1-yl)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   4-oxo-N-[(2-{[3-(2,2,2-trifluoroethoxy)azetidin-1-yl]methyl}-1H-indol-6-yl)methyl]-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[(2-{[3-(difluoromethyl)azetidin-1-yl]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-({2-[(3-methoxyazetidin-1-yl)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[(2-{[3-(tert-butoxy)azetidin-1-yl]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   4-oxo-N-[(2-{[3-(trifluoromethyl)azetidin-1-yl]methyl}-1H-indol-6-yl)methyl]-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-({2-[(3-ethoxyazetidin-1-yl)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-{[2-({2-azaspiro[3.5]nonan-2-yl}methyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-({2-[(2-methylazetidin-1-yl)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-({2-[(3,3-dimethylpyrrolidin-1-yl)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-{[2-({6-fluoro-2-azaspiro[3.3]heptanean-2-yl}methyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-{[2-({6,6-difluoro-2-azaspiro[3.3]heptanean-2-yl}methyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-({2-[(3-cyclobutylazetidin-1-yl)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-({2-[(3-cyclopropylazetidin-1-yl)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-({2-[(3-tert-butylazetidin-1-yl)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[(2-{[(1-tert-butylcyclopropyl)amino]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-{[2-({[(3-methylcyclobutyl)methyl]amino}methyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   4-oxo-N-[(2-{[(2,3,3-trimethylbutan-2-yl)amino]methyl}-1H-indol-6-yl)methyl]-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[(2-{[({imidazo[1,2-a]pyridin-2-yl}methyl)amino]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-({2-[(3,3-diethylazetidin-1-yl)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   4-oxo-N-[(2-{[(pent-3-yn-1-yl)amino]methyl}-1H-indol-6-yl)methyl]-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-{[2-({6-azaspiro[3.4]octan-6-yl}methyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-({2-[(2,2-dimethylpyrrolidin-1-yl)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-{[2-({octahydrocyclopenta[c]pyrrol-2-yl}methyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-{[2-({5-azaspiro[2.4]heptanean-5-yl}methyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[(2-{[({3-methoxybicyclo[1.1.1]pentan-1-yl}methyl)amino]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   4-oxo-N-[(2-{[({spiro[2.2]pentan-1-yl}methyl)amino]methyl}-1H-indol-6-yl)methyl]-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   4-oxo-N-({2-[({spiro[2.3]hexan-1-yl}amino)methyl]-1H-indol-6-yl}methyl)-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[(2-{[({3-cyanobicyclo[1.1.1]pentan-1-yl}methyl)amino]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-{[2-({1-oxa-6-azaspiro[3.4]octan-6-yl}methyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-{[2-({2-azaspiro[4.4]nonan-2-yl}methyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[(2-{[(1-methylcyclopentyl)amino]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-{[2-(hydroxymethyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[(2-{[(1-cyclobutylcyclopropyl)amino]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-{[2-({[(1-methylcyclobutyl)methyl]amino}methyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   4-oxo-N-[(2-{[({spiro[2.3]hexan-5-yl}methyl)amino]methyl}-1H-indol-6-yl)methyl]-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-({2-[({[3-(fluoromethyl)bicyclo[1.1.1]pentan-1-yl]methyl}amino)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[(2-{[(1-{3-fluorobicyclo[1.1.1]pentan-1-yl}ethyl)amino]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-({2-[(tert-butylamino)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   4-(1-{[2-({2-azaspiro[3.3]heptanean-2-yl}methyl)-1H-indol-6-yl]methyl}-1H-1,2,3-triazol-4-yl)-1H-indazole-   N-{[2-(2-{2-azaspiro[3.3]heptanean-2-yl}ethyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   ({3-fluorobicyclo[1.1.1]pentan-1-yl}methyl)({6-[(4-{imidazo[1,5-a]pyridin-8-yl}-1H-1,2,3-triazol-1-yl)methyl]-1H-indol-2-yl}methyl)amine-   N-[(2-{[({3-fluorobicyclo[1.1.1]pentan-1-yl}methyl)amino]methyl}-1H-indol-6-yl)methyl]-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-7-carboxamide-   N-[(2-{[({bicyclo[1.1.1]pentan-1-yl}methyl)amino]methyl}-1H-pyrrolo[3,2-b]pyridin-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[(2-{[({3-fluorobicyclo[1.1.1]pentan-1-yl}methyl)amino]methyl}-1H-pyrrolo[3,2-b]pyridin-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[(2-{[(cyclobutylmethyl)amino]methyl}-1H-pyrrolo[3,2-b]pyridin-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[(2-{[({3-methylbicyclo[1.1.1]pentan-1-yl}methyl)amino]methyl}-1H-pyrrolo[3,2-c]pyridin-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[(2-{[(cyclobutylmethyl)amino]methyl}-1H-pyrrolo[3,2-c]pyridin-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[(2-{[({bicyclo[1.1.1]pentan-1-yl}methyl)amino]methyl}-1H-pyrrolo[3,2-c]pyridin-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[(2-{[({3-fluorobicyclo[1.1.1]pentan-1-yl}methyl)amino]methyl}-1H-pyrrolo[3,2-c]182yridine-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[(2-{[(cyclobutylmethyl)amino]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H,6H,7H,8H,9H-pyrido[1,2-a]pyrimidine-2-carboxamide-   (cyclobutylmethyl)({6-[(4-{1H-pyrrolo[2,3-b]pyridin-5-yl}-1H-imidazol-1-yl)methyl]-1H-indol-2-yl}methyl)amine-   (cyclobutylmethyl)({6-[(4-{imidazo[1,5-a]pyridin-8-yl}-1H-1,2,3-triazol-1-yl)methyl]-1H-indol-2-yl}methyl)amine-   N-[(2-{[(2,2-dimethylpropyl)amino]methyl}-1H-indol-6-yl)methyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxamide-   N-[(2-{[(cyclobutylmethyl)amino]methyl}-1H-indol-6-yl)methyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxamide-   (cyclobutylmethyl)({6-[(4-{1H-pyrrolo[2,3-b]pyridin-5-yl}-1H-1,2,3-triazol-1-yl)methyl]-1H-indol-2-yl}methyl)amine-   N-[[2-(2-azabicyclo[2.2.1]heptanean-2-ylmethyl)-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[(3-fluoro-1-bicyclo[1.1.1]pentanyl)methyl]-1-[6-[(4-imidazo[1,5-a]pyridin-8-yltriazol-1-yl)methyl]-1H-pyrrolo[3,2-c]pyridin-2-yl]methanamine    (cyclobutylmethyl)[(6-{[1-(1H-indazol-4-yl)-1H-1,2,3-triazol-4-yl]methyl}-1H-indol-2-yl)methyl]amine-   [(3,3-difluorocyclobutyl)methyl][(6-{[1-(1H-indazol-4-yl)-1H-1,2,3-triazol-4-yl]methyl}-1H-indol-2-yl)methyl]amine-   (cyclobutylmethyl)[(6-{[1-(isoquinolin-4-yl)-1H-1,2,3-triazol-4-yl]methyl}-1H-indol-2-yl)methyl]amine-   (cyclobutylmethyl)({6-[(1-{imidazo[1,5-a]pyridin-8-yl}-1H-1,2,3-triazol-4-yl)methyl]-1H-indol-2-yl}methyl)amine-   3-[1-({2-[({(Bicyclo[1.1.1]pent-1-yl)methyl}amino)methyl]-1H-indol-6-yl}methyl)-1H-1,2,3-triazol-4-yl]-5-methoxy-2-pyridinecarbonitrile;-   3-[1-({2-[({(3-Fluorobicyclo[1.1.1]pent-1-yl)methyl}amino)methyl]-1H-indol-6-yl}methyl)-1H-1,2,3-triazol-4-yl]-5-methoxy-2-pyridinecarbonitrile;-   5-Methoxy-3-[1-({2-[({(3-methylbicyclo[1.1.1]pent-1-yl)methyl}amino)methyl]-1H-indol-6-yl}methyl)-1H-1,2,3-triazol-4-yl]-2-pyridinecarbonitrile;-   3-{1-[(2-{[(Cyclobutylmethyl)amino]methyl}-1H-indol-6-yl)methyl]-1H-1,2,3-triazol-4-yl}-5-methoxy-2-pyridinecarbonitrile;-   3-{1-[(2-{(6-Aza-6-spiro[3.4]octyl)methyl}-1H-indol-6-yl)methyl]-1H-1,2,3-triazol-4-yl}-5-methoxy-2-pyridinecarbonitrile;-   3-[1-({2-[(4,4-Dimethyl-1-piperidyl)methyl]-1H-indol-6-yl}methyl)-1H-1,2,3-triazol-4-yl]-5-methoxy-2-pyridinecarbonitrile;-   N-((2-((6-azaspiro[3.4]octan-6-yl)methyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   3-(1-((2-(((cyclobutylmethyl)amino)methyl)-1H-indol-6-yl)methyl)-1H-1,2,3-triazol-4-yl)-5-fluoropicolinonitrile-   1-cyclobutyl-N-((6-((4-(5-methoxypyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)-1H-indol-2-yl)methyl)methanamine;-   5-chloro-3-(1-((2-(((cyclobutylmethyl)amino)methyl)-1H-indol-6-yl)methyl)-1H-1,2,3-triazol-4-yl)picolinonitrile-   2-((6-azaspiro[3.4]octan-6-yl)methyl)-6-((4-(imidazo[1,5-a]pyridin-8-yl)-1H-1,2,3-triazol-1-yl)methyl)-1H-pyrrolo[3,2-c]pyridine.

Further compounds of the invention, or a pharmaceutically acceptablesalts thereof, include any one of the following:

-   3-[1-({2-[({(Bicyclo[1.1.1]pent-1-yl)methyl}amino)methyl]-1H-indol-6-yl}methyl)-1H-1,2,3-triazol-4-yl]-5-methoxy-2-pyridinecarbonitrile;-   3-[1-({2-[({(3-Fluorobicyclo[1.1.1]pent-1-yl)methyl}amino)methyl]-1H-indol-6-yl}methyl)-1H-1,2,3-triazol-4-yl]-5-methoxy-2-pyridinecarbonitrile;-   5-Methoxy-3-[1-({2-[({(3-methylbicyclo[1.1.1]pent-1-yl)methyl}amino)methyl]-1H-indol-6-yl}methyl)-1H-1,2,3-triazol-4-yl]-2-pyridinecarbonitrile;-   3-{1-[(2-{[(Cyclobutylmethyl)amino]methyl}-1H-indol-6-yl)methyl]-1H-1,2,3-triazol-4-yl}-5-methoxy-2-pyridinecarbonitrile;-   3-{1-[(2-{(6-Aza-6-spiro[3.4]octyl)methyl}-1H-indol-6-yl)methyl]-1H-1,2,3-triazol-4-yl}-5-methoxy-2-pyridinecarbonitrile;    and-   3-[1-({2-[(4,4-Dimethyl-1-piperidyl)methyl]-1H-indol-6-yl}methyl)-1H-1,2,3-triazol-4-yl]-5-methoxy-2-pyridinecarbonitrile.

Particular compounds of the present invention include any of thecompounds exemplified in the present application, or a pharmaceuticallyacceptable salt thereof, and, in particular, any of the following:

-   N-[[2-[[(1-hydroxycyclobutyl)methylamino]methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide;-   N-[[2-[[(1-fluorocyclobutyl)methylamino]methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide;-   N-[[2-[(4,4-dimethyl-1-piperidyl)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[[2-[(cyclobutylmethylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[[2-[(cyclobutylmethylamino)methyl]-1H-indol-6-yl]methyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxamide-   N-(cyclobutylmethyl)-1-[6-[[4-(1H-pyrazolo[4,3-c]pyridin-4-yl)triazol-1-yl]methyl]-1H-indol-2-yl]methanamine-   N-(cyclobutylmethyl)-1-[6-[[4-(1H-indazol-4-yl)triazol-1-yl]methyl]-1H-indol-2-yl]methanamine-   N-(cyclobutylmethyl)-1-[6-[[4-(1H-pyrrolo[2,3-b]pyridin-5-yl)triazol-1-yl]methyl]-1H-indol-2-yl]methanamine-   N-[[2-[(2,2-dimethylpropylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[[2-[(1-bicyclo[1.1.1]pentanylmethylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide-   1-[[[6-[[4-(1H-indazol-4-yl)triazol-1-yl]methyl]-1H-indol-2-yl]methylamino]methyl]cyclobutanol-   N-[[2-[[(3-fluoro-1-bicyclo[1.1.1]pentanyl)methylamino]methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[[2-[[(3,3-difluorocyclobutyl)methylamino]methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[(3,3-difluorocyclobutyl)methyl]-1-[6-[[1-(1H-indazol-4-yl)triazol-4-yl]methyl]-1H-indol-2-yl]methanamine-   N-[[2-[(oxetan-2-ylmethylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[[2-[(cyclobutylmethylamino)methyl]-1H-indol-6-yl]methyl]-1H-indazole-4-carboxamide-   N-[[2-[[(1-fluorocyclobutyl)methylamino]methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[[2-[(cyclobutylmethylamino)methyl]-3H-benzimidazol-5-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-(cyclobutylmethyl)-1-[6-[[1-(4-isoquinolyl)triazol-4-yl]methyl]-1H-indol-2-yl]methanamine-   4-oxo-N-[[2-[(prop-2-ynylamino)methyl]-1H-indol-6-yl]methyl]pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[[2-[(2,2-dimethylpropylamino)methyl]-1H-indol-6-yl]methyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxamide-   N-[[2-[(cyclopropylmethylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[[2-[(isobutylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[[2-[(cyclohexylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide.

The various functional groups and substituents making up the compoundsof the formula (I) are typically chosen such that the molecular weightof the compound of the formula (I) does not exceed 1000. More usually,the molecular weight of the compound will be less than 900, for exampleless than 800, or less than 750, or less than 700, or less than 650.More preferably, the molecular weight is less than 600 and, for example,is 550 or less.

A suitable pharmaceutically acceptable salt of a compound of theinvention is, for example, an acid-addition salt of a compound of theinvention which is sufficiently basic, for example, an acid-additionsalt with, for example, an inorganic or organic acid, for examplehydrochloric, hydrobromic, sulfuric, phosphoric, trifluoroacetic,formic, citric methane sulfonate or maleic acid. In addition, a suitablepharmaceutically acceptable salt of a compound of the invention which issufficiently acidic is an alkali metal salt, for example a sodium orpotassium salt, an alkaline earth metal salt, for example a calcium ormagnesium salt, an ammonium salt or a salt with an organic base whichaffords a pharmaceutically acceptable cation, for example a salt withmethylamine, dimethylamine, trimethylamine, piperidine, morpholine ortris-(2-hydroxyethyl)amine.

Compounds that have the same molecular formula but differ in the natureor sequence of bonding of their atoms or the arrangement of their atomsin space are termed “isomers”. Isomers that differ in the arrangement oftheir atoms in space are termed “stereoisomers”. Stereoisomers that arenot mirror images of one another are termed “diastereomers” and thosethat are non-superimposable mirror images of each other are termed“enantiomers”. When a compound has an asymmetric center, for example, itis bonded to four different groups, a pair of enantiomers is possible.An enantiomer can be characterized by the absolute configuration of itsasymmetric center and is described by the R- and S-sequencing rules ofCahn and Prelog, or by the manner in which the molecule rotates theplane of polarized light and designated as dextrorotatory orlevorotatory (i.e., as (+) or (−)-isomers respectively). A chiralcompound can exist as either individual enantiomer or as a mixturethereof. A mixture containing equal proportions of the enantiomers iscalled a “racemic mixture”.

The compounds of this invention may possess one or more asymmetriccenters; such compounds can therefore be produced as individual (R)- or(S)-stereoisomers or as mixtures thereof. Unless indicated otherwise,the description or naming of a particular compound in the specificationand claims is intended to include both individual enantiomers andmixtures, racemic or otherwise, thereof. The methods for thedetermination of stereochemistry and the separation of stereoisomers arewell-known in the art (see discussion in Chapter 4 of “Advanced OrganicChemistry”, 4th edition J. March, John Wiley and Sons, New York, 2001),for example by synthesis from optically active starting materials or byresolution of a racemic form. Some of the compounds of the invention mayhave geometric isomeric centres (E- and Z-isomers). It is to beunderstood that the present invention encompasses all optical,diastereoisomers and geometric isomers and mixtures thereof that possessantiproliferative activity.

The present invention also encompasses compounds of the invention asdefined herein which comprise one or more isotopic substitutions. Forexample, H may be in any isotopic form, including ¹H, ²H(D), and ³H (T);C may be in any isotopic form, including ¹²C, ¹³C, and ¹⁴C; and O may bein any isotopic form, including ¹⁶O and ¹⁸O; and the like.

It is also to be understood that certain compounds of the formula (I)(and compounds of formula (II), (Ill) and (IV)) may exist in solvated aswell as unsolvated forms such as, for example, hydrated forms. It is tobe understood that the invention encompasses all such solvated formsthat possess antiproliferative activity.

It is also to be understood that certain compounds of the formula (I)(and compounds of formula (II), (Ill) and (IV)) may exhibitpolymorphism, and that the invention encompasses all such forms thatpossess antiproliferative activity.

Compounds of the formula (I) (and compounds of formula (II), (Ill) and(IV)) may exist in a number of different tautomeric forms and referencesto compounds of the formula (I) include all such forms. For theavoidance of doubt, where a compound can exist in one of severaltautomeric forms, and only one is specifically described or shown, allothers are nevertheless embraced by formula (I). Examples of tautomericforms include keto-, enol-, and enolate-forms, as in, for example, thefollowing tautomeric pairs: keto/enol (illustrated below),imine/enamine, amide/imino alcohol, amidine/amidine, nitroso/oxime,thioketone/enethiol, and nitro/aci-nitro.

Compounds of the formula (I) containing an amine function may also formN-oxides. A reference herein to a compound of the formula (I) thatcontains an amine function also includes the N-oxide. Where a compoundcontains several amine functions, one or more than one nitrogen atom maybe oxidised to form an N-oxide. Particular examples of N-oxides are theN-oxides of a tertiary amine or a nitrogen atom of a nitrogen-containingheterocycle. N-Oxides can be formed by treatment of the correspondingamine with an oxidizing agent such as hydrogen peroxide or a per-acid(e.g. a peroxycarboxylic acid), see for example Advanced OrganicChemistry, by Jerry March, 4^(th) Edition, Wiley Interscience, pages.More particularly, N-oxides can be made by the procedure of L. W. Deady(Syn. Comm. 1977, 7, 509-514) in which the amine compound is reactedwith m-chloroperoxybenzoic acid (mCPBA), for example, in an inertsolvent such as dichloromethane.

The compounds of formula (I) may be administered in the form of apro-drug which is broken down in the human or animal body to release acompound of the invention. A pro-drug may be used to alter the physicalproperties and/or the pharmacokinetic properties of a compound of theinvention. A pro-drug can be formed when the compound of the inventioncontains a suitable group or substituent to which a property-modifyinggroup can be attached. Examples of pro-drugs include in vivo cleavableester derivatives that may be formed at a carboxy group or a hydroxygroup in a compound of the formula (I) and in-vivo cleavable amidederivatives that may be formed at a carboxy group or an amino group in acompound of the formula (I).

Accordingly, the present invention includes those compounds of theformula I as defined hereinbefore when made available by organicsynthesis and when made available within the human or animal body by wayof cleavage of a pro-drug thereof. Accordingly, the present inventionincludes those compounds of the formula (I) that are produced by organicsynthetic means and also such compounds that are produced in the humanor animal body by way of metabolism of a precursor compound, that is acompound of the formula (I) may be a synthetically-produced compound ora metabolically-produced compound.

A suitable pharmaceutically acceptable pro-drug of a compound of theformula (I) is one that is based on reasonable medical judgement asbeing suitable for administration to the human or animal body withoutundesirable pharmacological activities and without undue toxicity.

Various forms of pro-drug have been described, for example in thefollowing documents:

a) Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, etal. (Academic Press, 1985);b) Design of Pro-drugs, edited by H. Bundgaard, (Elsevier, 1985);c) A Textbook of Drug Design and Development, edited byKrogsgaard-Larsen and H. Bundgaard, Chapter 5 “Design and Application ofPro-drugs”, by H. Bundgaard p. 113-191 (1991);

d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); e) H.Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988);

f) N. Kakeya, et al., Chem. Pharm. Bull., 32, 692 (1984);

g) T. Higuchi and V. Stella, “Pro-Drugs as Novel Delivery Systems”,A.C.S. Symposium Series, Volume 14; and

h) E. Roche (editor), “Bioreversible Carriers in Drug Design”, PergamonPress, 1987.

A suitable pharmaceutically acceptable pro-drug of a compound of theformula (I) that possesses a carboxy group is, for example, an in vivocleavable ester thereof. An in vivo cleavable ester of a compound of theformula (I) containing a carboxy group is, for example, apharmaceutically acceptable ester which is cleaved in the human oranimal body to produce the parent acid. Suitable pharmaceuticallyacceptable esters for carboxy include C₁₋₆alkyl esters such as methyl,ethyl and tert-butyl, C₁₋₆alkoxymethyl esters such as methoxymethylesters, C₁₋₆alkanoyloxymethyl esters such as pivaloyloxymethyl esters,3-phthalidyl esters, C₃₋₈cycloalkylcarbonyloxy-C₁₋₆alkyl esters such ascyclopentylcarbonyloxymethyl and 1-cyclohexylcarbonyloxyethyl esters,2-oxo-1,3-dioxolenylmethyl esters such as5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl esters andC₁₋₆alkoxycarbonyloxy-C₁₋₆alkyl esters such as methoxycarbonyloxymethyland 1-methoxycarbonyloxyethyl esters.

A suitable pharmaceutically acceptable pro-drug of a compound of theformula (I) that possesses a hydroxy group is, for example, an in vivocleavable ester or ether thereof. An in vivo cleavable ester or ether ofa compound of the formula (I) containing a hydroxy group is, forexample, a pharmaceutically acceptable ester or ether which is cleavedin the human or animal body to produce the parent hydroxy compound.Suitable pharmaceutically acceptable ester forming groups for a hydroxygroup include inorganic esters such as phosphate esters (includingphosphoramidic cyclic esters). Further suitable pharmaceuticallyacceptable ester forming groups for a hydroxy group includeC₁₋₁₀alkanoyl groups such as acetyl, benzoyl, phenylacetyl andsubstituted benzoyl and phenylacetyl groups, C₁₋₁₀alkoxycarbonyl groupssuch as ethoxycarbonyl, N,N—(C₁₋₆)₂carbamoyl, 2-dialkylaminoacetyl and2-carboxyacetyl groups. Examples of ring substituents on thephenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl,N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl and4-(C₁₋₄alkyl)piperazin-1-ylmethyl. Suitable pharmaceutically acceptableether forming groups for a hydroxy group include α-acyloxyalkyl groupssuch as acetoxymethyl and pivaloyloxymethyl groups.

A suitable pharmaceutically acceptable pro-drug of a compound of theformula (I) that possesses a carboxy group is, for example, an in vivocleavable amide thereof, for example an amide formed with an amine suchas ammonia, a C₁₋₄alkylamine such as methylamine, a (C₁₋₄alkyl)₂aminesuch as dimethylamine, N-ethyl-N-methylamine or diethylamine, aC₁₋₄alkoxy-C₂₋₄alkylamine such as 2-methoxyethylamine, a phenyl-C₁₋₄alkylamine such as benzylamine and amino acids such as glycine or anester thereof.

A suitable pharmaceutically acceptable pro-drug of a compound of theformula (I) that possesses an amino group is, for example, an in vivocleavable amide derivative thereof. Suitable pharmaceutically acceptableamides from an amino group include, for example an amide formed withC₁₋₁₀alkanoyl groups such as an acetyl, benzoyl, phenylacetyl andsubstituted benzoyl and phenylacetyl groups. Examples of ringsubstituents on the phenylacetyl and benzoyl groups include aminomethyl,N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl,piperazin-1-ylmethyl and 4-(C₁₋₄alkyl)piperazin-1-ylmethyl.

The in vivo effects of a compound of the formula (I) may be exerted inpart by one or more metabolites that are formed within the human oranimal body after administration of a compound of the formula (I). Asstated hereinbefore, the in vivo effects of a compound of the formula(I) may also be exerted by way of metabolism of a precursor compound (apro-drug).

Though the present invention may relate to any compound or particulargroup of compounds defined herein by way of optional, preferred orsuitable features or otherwise in terms of particular embodiments, thepresent invention may also relate to any compound or particular group ofcompounds that specifically excludes said optional, preferred orsuitable features or particular embodiments.

Suitably, the present invention excludes any individual compounds notpossessing the biological activity defined herein.

Synthesis

The compounds of the present invention can be prepared by any suitabletechnique known in the art. Particular processes for the preparation ofthese compounds are described further in the accompanying examples.

In the description of the synthetic methods described herein and in anyreferenced synthetic methods that are used to prepare the startingmaterials, it is to be understood that all proposed reaction conditions,including choice of solvent, reaction atmosphere, reaction temperature,duration of the experiment and workup procedures, can be selected by aperson skilled in the art.

It is understood by one skilled in the art of organic synthesis that thefunctionality present on various portions of the molecule must becompatible with the reagents and reaction conditions utilised.

It will be appreciated that during the synthesis of the compounds of theinvention in the processes defined herein, or during the synthesis ofcertain starting materials, it may be desirable to protect certainsubstituent groups to prevent their undesired reaction. The skilledchemist will appreciate when such protection is required, and how suchprotecting groups may be put in place, and later removed.

For examples of protecting groups see one of the many general texts onthe subject, for example, ‘Protective Groups in Organic Synthesis’ byTheodora Green (publisher: John Wiley & Sons). Protecting groups may beremoved by any convenient method described in the literature or known tothe skilled chemist as appropriate for the removal of the protectinggroup in question, such methods being chosen so as to effect removal ofthe protecting group with the minimum disturbance of groups elsewhere inthe molecule.

Thus, if reactants include, for example, groups such as amino, carboxyor hydroxy it may be desirable to protect the group in some of thereactions mentioned herein.

By way of example, a suitable protecting group for an amino oralkylamino group is, for example, an acyl group, for example an alkanoylgroup such as acetyl, an alkoxycarbonyl group, for example amethoxycarbonyl, ethoxycarbonyl or t-butoxycarbonyl group, anarylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroylgroup, for example benzoyl. The deprotection conditions for the aboveprotecting groups necessarily vary with the choice of protecting group.Thus, for example, an acyl group such as an alkanoyl or alkoxycarbonylgroup or an aroyl group may be removed by, for example, hydrolysis witha suitable base such as an alkali metal hydroxide, for example lithiumor sodium hydroxide. Alternatively an acyl group such as atert-butoxycarbonyl group may be removed, for example, by treatment witha suitable acid as hydrochloric, sulfuric or phosphoric acid ortrifluoroacetic acid and an arylmethoxycarbonyl group such as abenzyloxycarbonyl group may be removed, for example, by hydrogenationover a catalyst such as palladium-on-carbon, or by treatment with aLewis acid for example boron tris(trifluoroacetate). A suitablealternative protecting group for a primary amino group is, for example,a phthaloyl group which may be removed by treatment with an alkylamine,for example dimethylaminopropylamine, or with hydrazine.

A suitable protecting group for a hydroxy group is, for example, an acylgroup, for example an alkanoyl group such as acetyl, an aroyl group, forexample benzoyl, or an arylmethyl group, for example benzyl. Thedeprotection conditions for the above protecting groups will necessarilyvary with the choice of protecting group. Thus, for example, an acylgroup such as an alkanoyl or an aroyl group may be removed, for example,by hydrolysis with a suitable base such as an alkali metal hydroxide,for example lithium, sodium hydroxide or ammonia. Alternatively anarylmethyl group such as a benzyl group may be removed, for example, byhydrogenation over a catalyst such as palladium-on-carbon.

A suitable protecting group for a carboxy group is, for example, anesterifying group, for example a methyl or an ethyl group which may beremoved, for example, by hydrolysis with a base such as sodiumhydroxide, or for example a t-butyl group which may be removed, forexample, by treatment with an acid, for example an organic acid such astrifluoroacetic acid, or for example a benzyl group which may beremoved, for example, by hydrogenation over a catalyst such aspalladium-on-carbon.

Resins may also be used as a protecting group.

The methodology employed to synthesise a compound of formula I will varydepending on the nature of the variable groups. Suitable processes fortheir preparation are described further in the accompanying Examples.

Once a compound of formula I has been synthesised by any one of theprocesses defined herein, the processes may then further comprise theadditional steps of:

(i) removing any protecting groups present;(ii) converting the compound formula I into another compound of formulaI;(iii) forming a pharmaceutically acceptable salt, hydrate or solvatethereof; and/or(iv) forming a prodrug thereof.

The resultant compounds of formula I can be isolated and purified usingtechniques well known in the art.

Biological Activity

The METTL3 enzyme and cell assays described in accompanying Examplesection may be used to measure the pharmacological effects of thecompounds of the present invention.

Although the pharmacological properties of the compounds of formula Ivary with structural change, as expected, the compounds of the inventionwere found to be active in these METTL3 assays.

In general, the compounds of the invention demonstrate an IC₅₀ of 10 μMor less in the METTL3 enzyme assay described herein, with preferredcompounds of the invention demonstrating an IC₅₀ of 5 μM or less and themost preferred compounds of the invention demonstrating an IC₅₀ of 2 μMor less.

In the METTL3 cell assay described in the Example section, the compoundsof formula (I) suitably possess an activity of less than 10 μM, withpreferred compounds of the invention demonstrating an IC₅₀ of 5 μM orless and the most preferred compounds demonstrating an activity of 2 μMor less.

Pharmaceutical Compositions

According to a further aspect of the invention there is provided apharmaceutical composition which comprises a compound of the inventionas defined hereinbefore, or a pharmaceutically acceptable salt thereof,and one or more pharmaceutically acceptable excipients.

The compositions of the invention may be in a form suitable for oral use(for example as tablets, lozenges, hard or soft capsules, aqueous oroily suspensions, emulsions, dispersible powders or granules, syrups orelixirs), for topical use (for example as creams, ointments, gels, oraqueous or oily solutions or suspensions), for administration byinhalation (for example as a finely divided powder or a liquid aerosol),for administration by insufflation (for example as a finely dividedpowder) or for parenteral administration (for example as a sterileaqueous or oily solution for intravenous, subcutaneous, intramuscular,intraperitoneal or intramuscular dosing or as a suppository for rectaldosing).

The compositions of the invention may be obtained by conventionalprocedures using conventional pharmaceutical excipients, well known inthe art. Thus, compositions intended for oral use may contain, forexample, one or more colouring, sweetening, flavouring and/orpreservative agents.

An effective amount of a compound of the present invention for use intherapy is an amount sufficient to treat or prevent a proliferativecondition and/or treat or prevent an autoimmune disease referred toherein, slow its progression and/or reduce the symptoms associated withthe condition and/or disease.

The amount of active ingredient that is combined with one or moreexcipients to produce a single dosage form will necessarily varydepending upon the individual treated and the particular route ofadministration. For example, a formulation intended for oraladministration to humans will generally contain, for example, from 0.5mg to 0.5 g of active agent (more suitably from 0.5 to 100 mg, forexample from 1 to 30 mg) compounded with an appropriate and convenientamount of excipients which may vary from about 5 to about 98 percent byweight of the total composition.

The size of the dose for therapeutic or prophylactic purposes of acompound of the formula (I) will naturally vary according to the natureand severity of the conditions, the age and sex of the animal or patientand the route of administration, according to well known principles ofmedicine.

In using a compound of the invention for therapeutic or prophylacticpurposes it will generally be administered so that a daily dose in therange, for example, 0.1 mg/kg to 75 mg/kg body weight is received, givenif required in divided doses. In general lower doses will beadministered when a parenteral route is employed. Thus, for example, forintravenous or intraperitoneal administration, a dose in the range, forexample, 0.1 mg/kg to 30 mg/kg body weight will generally be used.Similarly, for administration by inhalation, a dose in the range, forexample, 0.05 mg/kg to 25 mg/kg body weight will be used. Oraladministration may also be suitable, particularly in tablet form.Typically, unit dosage forms will contain about 0.5 mg to 0.5 g of acompound of this invention.

Therapeutic Uses and Applications

The present invention provides compounds that function as inhibitors ofMETTL3 activity.

The present invention therefore provides a method of inhibiting METTL3activity in vitro or in vivo, said method comprising contacting a cellwith an effective amount of a compound, or a pharmaceutically acceptablesalt thereof, or a pharmaceutical composition as defined herein.

The present invention also provides a method of treating a disease ordisorder in which METTL3 activity is implicated in a patient in need ofsuch treatment, said method comprising administering to said patient atherapeutically effective amount of a compound, or a pharmaceuticallyacceptable salt thereof, or a pharmaceutical composition as definedherein. Suitably, the disease or disorder in which METTL3 activity isimplicated is cancer, such as lung cancer, renal cancer, solid organcancer, pancreatic cancer or leukaemia, type 2 diabetes, aneuropsychiatric behavioural disorder, infection (e.g. viral infection)or a depressive disorder.

The present invention provides a method of inhibiting cellproliferation, in vitro or in vivo, said method comprising contacting acell with an effective amount of a compound, or a pharmaceuticallyacceptable salt thereof, as defined herein.

The present invention provides a method of treating a proliferativedisorder, said method comprising administering to a subject in needthereof a therapeutically effective amount of a compound, or apharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition as defined herein.

The present invention provides a method of treating cancer, said methodcomprising administering to a subject in need thereof a therapeuticallyeffective amount of a compound, or a pharmaceutically acceptable saltthereof, or a pharmaceutical composition as defined herein. Suitably thecancer is lung cancer, renal cancer, solid organ cancer, pancreaticcancer or leukaemia suitably AML leukaemia or chronic myeloid leukaemia.

The present invention provides a method of treating leukaemia, saidmethod comprising administering to a subject in need thereof atherapeutically effective amount of a compound, or a pharmaceuticallyacceptable salt thereof, or a pharmaceutical composition as definedherein.

The present invention provides a method of treating AML leukaemia, saidmethod comprising administering to a subject in need thereof atherapeutically effective amount of a compound, or a pharmaceuticallyacceptable salt thereof, or a pharmaceutical composition as definedherein.

The present invention provides a method of treating an autoimmunedisease, said method comprising administering to a subject in needthereof a therapeutically effective amount of a compound, or apharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition as defined herein. Suitably the autoimmune disease iscolitis, multiple sclerosis, rheumatoid arthritis, lupus, cirrhosis, ordermatitis.

The present invention provides a method of treating a neurologicaldisease, said method comprising administering to a subject in needthereof a therapeutically effective amount of a compound, or apharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition as defined herein.

The present invention provides a method of treating an infectiousdisease, said method comprising administering to a subject in needthereof a therapeutically effective amount of a compound, or apharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition as defined herein.

In another aspect, the present invention provides a method of treating aviral infection, said method comprising administering to a subject inneed thereof a therapeutically effective amount of a compound as definedherein, or a pharmaceutically acceptable salt, or a pharmaceuticalcomposition as defined herein. Suitably, the viral infection is a RNAviral infection. Suitably, the viral infection is human papillomavirus(HPV) or hepatitis.

The present invention provides a method of treating an inflammatorydisease, said method comprising administering to a subject in needthereof a therapeutically effective amount of a compound, or apharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition as defined herein.

METTL3 inhibitors are also potentially useful therapeutic agents fortreating diseases related to the re-activation of the silencedX-chromosome (Patil et al, Nature, 2016 Sep. 15;537(7620):369-373). Assuch, they are potentially effective therapeutic agents for thetreatment of Rett syndrome.

The present invention further provides a method of treating a diseaserelated to the re-activation of the silenced X-chromosome, said methodcomprising administering to a subject in need thereof a therapeuticallyeffective amount of a compound, or a pharmaceutically acceptable saltthereof, or a pharmaceutical composition as defined herein.

The present invention further provides a method of treating Rettsyndrome, said method comprising administering to a subject in needthereof a therapeutically effective amount of a compound, or apharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition as defined herein.

The present invention provides a compound, or a pharmaceuticallyacceptable salt thereof, or a pharmaceutical composition as definedherein for use in therapy.

The present invention provides a compound, or a pharmaceuticallyacceptable salt thereof, or a pharmaceutical composition as definedherein for use in the treatment of a proliferative condition.

The present invention provides a compound, or a pharmaceuticallyacceptable salt thereof, or a pharmaceutical composition as definedherein for use in the treatment of cancer. In a particular embodiment,the cancer is human cancer. Suitably the cancer is lung cancer, renalcancer, solid organ cancer, pancreatic cancer or leukaemia suitably AMLleukaemia or chronic myeloid leukaemia.

The present invention provides a compound, or a pharmaceuticallyacceptable salt thereof, or a pharmaceutical composition as definedherein for use in the treatment of leukaemia.

The present invention provides a compound, or a pharmaceuticallyacceptable salt thereof, or a pharmaceutical composition as definedherein for use in the treatment of AML leukaemia.

The present invention provides a compound, or a pharmaceuticallyacceptable salt thereof, or a pharmaceutical composition as definedherein for use in the inhibition of METTL3 activity.

The present invention provides a compound, or a pharmaceuticallyacceptable salt thereof, or a pharmaceutical composition as definedherein for use in the treatment of an autoimmune disease. Suitably theautoimmune disease is colitis, multiple sclerosis, rheumatoid arthritis,lupus, cirrhosis, or dermatitis.

The present invention provides a compound, or a pharmaceuticallyacceptable salt thereof, or a pharmaceutical composition as definedherein for use in the treatment of an neurological disease.

The present invention provides a compound, or a pharmaceuticallyacceptable salt thereof, or a pharmaceutical composition as definedherein for use in the treatment of an infectious disease.

The present invention provides a compound, or a pharmaceuticallyacceptable salt thereof, or a pharmaceutical composition as definedherein for use in the treatment of an inflammatory disease.

In another aspect, the present invention provides a compound as definedherein, or a pharmaceutically acceptable salt thereof, or apharmaceutical composition as defined herein, for use in the treatmentof a viral infection. Suitably, the viral infection is a RNA viralinfection. Suitably, the viral infection is human papillomavirus (HPV)or hepatitis.

The present invention provides a compound, or a pharmaceuticallyacceptable salt thereof, as defined herein for use in the treatment of adisease or disorder in which METTL3 activity is implicated. Suitably,the disease or disorder in which METTL3 activity is implicated iscancer, such as lung cancer, renal cancer, solid organ cancer,pancreatic cancer or leukaemia, type 2 diabetes, a neuropsychiatricbehavioural disorder or a depressive disorder.

The present invention provides a compound, or a pharmaceuticallyacceptable salt thereof, or a pharmaceutical composition as definedherein, for use in the treatment of a disease related to there-activation of the silenced X-chromosome.

The present invention provides a compound, or a pharmaceuticallyacceptable salt thereof, or a pharmaceutical composition as definedherein, for use in the treatment of Rett syndrome.

The present invention provides a use of a compound, or apharmaceutically acceptable salt thereof, as defined herein in themanufacture of a medicament for the treatment of a proliferativecondition.

The present invention provides a use of a compound, or apharmaceutically acceptable salt thereof, as defined herein in themanufacture of a medicament for the treatment of cancer. Suitably, themedicament is for use in the treatment of human cancers.

Suitably the cancer is lung cancer, renal cancer, solid organ cancer,pancreatic cancer or leukaemia suitably AML leukaemia or chronic myeloidleukaemia.

The present invention provides a use of a compound, or apharmaceutically acceptable salt thereof, as defined herein in themanufacture of a medicament for the treatment of leukaemia.

The present invention provides a use of a compound, or apharmaceutically acceptable salt thereof, as defined herein in themanufacture of a medicament for the treatment of AML leukaemia.

The present invention provides a use of a compound, or apharmaceutically acceptable salt thereof, as defined herein in themanufacture of a medicament for the treatment of an autoimmune disease.Suitably the autoimmune disease is colitis, multiple sclerosis,rheumatoid arthritis, lupus, cirrhosis, or dermatitis.

The present invention provides a use of a compound, or apharmaceutically acceptable salt thereof, as defined herein in themanufacture of a medicament for the treatment of a neurological disease.

The present invention provides a use of a compound, or apharmaceutically acceptable salt thereof, as defined herein in themanufacture of a medicament for the treatment of an inflammatorydisease.

In another aspect, the present invention provides the use of a compoundas defined herein, or a pharmaceutically acceptable salt thereof, in themanufacture of a medicament for use in the treatment of a viralinfection. Suitably, the viral infection is a RNA viral infection.Suitably, the viral infection is human papillomavirus (HPV) orhepatitis.

The present invention provides a use of a compound, or apharmaceutically acceptable salt thereof, as defined herein in themanufacture of a medicament for the treatment of an infectious disease.

The present invention provides a use of a compound, or apharmaceutically acceptable salt thereof, as defined herein in themanufacture of a medicament for the inhibition of METTL3 activity.

The present invention provides a use of a compound, or apharmaceutically acceptable salt thereof, as defined herein in themanufacture of a medicament for the treatment of a disease or disorderin which METTL3 activity is implicated. Suitably, the disease ordisorder in which METTL3 activity is implicated is cancer, such as lungcancer, renal cancer, solid organ cancer, pancreatic cancer orleukaemia, type 2 diabetes, a neuropsychiatric behavioural disorder or adepressive disorder.

The present invention provides a use of a compound, or apharmaceutically acceptable salt thereof, as defined herein in themanufacture of a medicament for the treatment of a disease related tothe re-activation of the silenced X-chromosome.

The present invention provides a use of a compound, or apharmaceutically acceptable salt thereof, as defined herein in themanufacture of a medicament for the treatment of Rett syndrome.

The term “proliferative disorder” are used interchangeably herein andpertain to an unwanted or uncontrolled cellular proliferation ofexcessive or abnormal cells which is undesired, such as, neoplastic orhyperplastic growth, whether in vitro or in vivo. Examples ofproliferative conditions include, but are not limited to, pre-malignantand malignant cellular proliferation, including but not limited to,malignant neoplasms and tumours, cancers, leukemias, psoriasis, bonediseases, fibroproliferative disorders (e.g., of connective tissues),and atherosclerosis. Any type of cell may be treated, including but notlimited to, lung, colon, breast, ovarian, prostate, liver, pancreas,brain and skin.

The anti-proliferative effects of the compounds of the present inventionhave particular application in the treatment of human cancers (by virtueof their inhibition of METTL3 activity).

The anti-cancer effect may arise through one or more mechanisms,including but not limited to, the regulation of cell proliferation, theinhibition of angiogenesis (the formation of new blood vessels), theinhibition of metastasis (the spread of a tumour from its origin), theinhibition of invasion (the spread of tumour cells into neighbouringnormal structures), or the promotion of apoptosis (programmed celldeath).

In a particular embodiment of the invention, the proliferative conditionto be treated is cancer.

Routes of Administration

The compounds of the invention or pharmaceutical compositions comprisingthese compounds may be administered to a subject by any convenient routeof administration, whether systemically/peripherally or topically (i.e.,at the site of desired action).

Routes of administration include, but are not limited to, oral (e.g, byingestion); buccal; sublingual; transdermal (including, e.g., by apatch, plaster, etc.); transmucosal (including, e.g., by a patch,plaster, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eyedrops); pulmonary (e.g., by inhalation or insufflation therapy using,e.g., via an aerosol, e.g., through the mouth or nose); rectal (e.g., bysuppository or enema); vaginal (e.g., by pessary); parenteral, forexample, by injection, including subcutaneous, intradermal,intramuscular, intravenous, intra-arterial, intracardiac, intrathecal,intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal,intratracheal, subcuticular, intraarticular, subarachnoid, andintrasternal; by implant of a depot or reservoir, for example,subcutaneously or intramuscularly.

Combination Therapies

The antiproliferative treatment defined hereinbefore may be applied as asole therapy or may involve, in addition to the compound of theinvention, conventional surgery or radiotherapy or chemotherapy. Suchchemotherapy may include one or more of the following categories ofanti-tumour agents:

(i) other antiproliferative/antineoplastic drugs and combinationsthereof, as used in medical oncology, such as alkylating agents (forexample cis-platin, oxaliplatin, carboplatin, cyclophosphamide, nitrogenmustard, melphalan, chlorambucil, busulphan, temozolamide andnitrosoureas); antimetabolites (for example gemcitabine and antifolatessuch as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed,methotrexate, cytosine arabinoside, and hydroxyurea); antitumourantibiotics (for example anthracyclines like adriamycin, bleomycin,doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C,dactinomycin and mithramycin); antimitotic agents (for example vincaalkaloids like vincristine, vinblastine, vindesine and vinorelbine andtaxoids like taxol and taxotere and polokinase inhibitors); andtopoisomerase inhibitors (for example epipodophyllotoxins like etoposideand teniposide, amsacrine, topotecan and camptothecin);(ii) cytostatic agents such as antioestrogens (for example tamoxifen,fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene),antiandrogens (for example bicalutamide, flutamide, nilutamide andcyproterone acetate), LHRH antagonists or LHRH agonists (for examplegoserelin, leuprorelin and buserelin), progestogens (for examplemegestrol acetate), aromatase inhibitors (for example as anastrozole,letrozole, vorazole and exemestane) and inhibitors of 5α-reductase suchas finasteride;(iii) anti-invasion agents [for example c-Src kinase family inhibitorslike4-(6-chloro-2,3-methylenedioxyanilino)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-tetrahydropyran-4-yloxyquinazoline(AZD0530; International Patent Application WO 01/94341),N-(2-chloro-6-methylphenyl)-2-{6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4-ylamino}thiazole-5-carboxamide(dasatinib, BMS-354825; J. Med. Chem., 2004, 47, 6658-6661) andbosutinib (SKI-606), and metalloproteinase inhibitors like marimastat,inhibitors of urokinase plasminogen activator receptor function orantibodies to Heparanase];(iv) inhibitors of growth factor function: for example such inhibitorsinclude growth factor antibodies and growth factor receptor antibodies(for example the anti-erbB2 antibody trastuzumab [Herceptin™], theanti-EGFR antibody panitumumab, the anti-erbB1 antibody cetuximab[Erbitux, C225] and any growth factor or growth factor receptorantibodies disclosed by Stern et al. (Critical reviews inoncology/haematology, 2005, Vol. 54, pp 11-29); such inhibitors alsoinclude tyrosine kinase inhibitors, for example inhibitors of theepidermal growth factor family (for example EGFR family tyrosine kinaseinhibitors such asN-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine(gefitinib, ZD1839),N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine(erlotinib, OSI-774) and6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)-quinazolin-4-amine(Cl 1033), erbB2 tyrosine kinase inhibitors such as lapatinib);inhibitors of the hepatocyte growth factor family; inhibitors of theinsulin growth factor family; inhibitors of the platelet-derived growthfactor family such as imatinib and/or nilotinib (AMN107); inhibitors ofserine/threonine kinases (for example Ras/Raf signalling inhibitors suchas farnesyl transferase inhibitors, for example sorafenib (BAY 43-9006),tipifarnib (R115777) and lonafarnib (SCH66336)), inhibitors of cellsignalling through MEK and/or AKT kinases, c-kit inhibitors, abl kinaseinhibitors, PI3 kinase inhibitors, Plt3 kinase inhibitors, CSF-1R kinaseinhibitors, IGF receptor (insulin-like growth factor) kinase inhibitors;aurora kinase inhibitors (for example AZD1152, PH739358, VX-680,MLN8054, R763, MP235, MP529, VX-528 AND AX39459) and cyclin dependentkinase inhibitors such as CDK2 and/or CDK4 inhibitors;(v) antiangiogenic agents such as those which inhibit the effects ofvascular endothelial growth factor, [for example the anti-vascularendothelial cell growth factor antibody bevacizumab (Avastin™) and forexample, a VEGF receptor tyrosine kinase inhibitor such as vandetanib(ZD6474), vatalanib (PTK787), sunitinib (SU11248), axitinib (AG-013736),pazopanib (GW 786034) and4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline(AZD2171; Example 240 within WO 00/47212), compounds such as thosedisclosed in International Patent Applications WO97/22596, WO 97/30035,WO 97/32856 and WO 98/13354 and compounds that work by other mechanisms(for example linomide, inhibitors of integrin αvβ3 function andangiostatin)];(vi) vascular damaging agents such as Combretastatin A4 and compoundsdisclosed in International Patent Applications WO 99/02166, WO 00/40529,WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213;(vii) an endothelin receptor antagonist, for example zibotentan (ZD4054)or atrasentan;(viii) antisense therapies, for example those which are directed to thetargets listed above, such as ISIS 2503, an anti-ras antisense;(ix) gene therapy approaches, including for example approaches toreplace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2,GDEPT (gene-directed enzyme pro-drug therapy) approaches such as thoseusing cytosine deaminase, thymidine kinase or a bacterial nitroreductaseenzyme and approaches to increase patient tolerance to chemotherapy orradiotherapy such as multi-drug resistance gene therapy;(x) immunotherapy approaches, including for example ex-vivo and in-vivoapproaches to increase the immunogenicity of patient tumour cells, suchas transfection with cytokines such as interleukin 2, interleukin 4 orgranulocyte-macrophage colony stimulating factor, approaches to decreaseT-cell anergy, approaches using transfected immune cells such ascytokine-transfected dendritic cells, approaches usingcytokine-transfected tumour cell lines and approaches usinganti-idiotypic antibodies; and(xi) Agents used to treat AML leukaemia, including for example,cytarabine, FLT3 inhibitors, BCL2 inhibitors (e.g. venetoclax) or IDH1/2inhibitors.

In a particular embodiment, the antiproliferative treatment definedhereinbefore may involve, in addition to the compound of the invention,conventional surgery or radiotherapy or chemotherapy.

Such conjoint treatment may be achieved by way of the simultaneous,sequential or separate dosing of the individual components of thetreatment. Such combination products employ the compounds of thisinvention within the dosage range described hereinbefore and the otherpharmaceutically-active agent within its approved dosage range.

According to this aspect of the invention there is provided acombination for use in the treatment of a cancer (for example a cancerinvolving a solid tumour) comprising a compound of the invention asdefined hereinbefore, or a pharmaceutically acceptable salt thereof, andanother anti-tumour agent.

According to this aspect of the invention there is provided acombination for use in the treatment of a proliferative condition, suchas cancer (for example a cancer involving a solid tumour), comprising acompound of the invention as defined hereinbefore, or a pharmaceuticallyacceptable salt thereof, and any one of the anti-tumour agents listedherein above.

In a further aspect of the invention there is provided a compound of theinvention or a pharmaceutically acceptable salt thereof, for use in thetreatment of cancer in combination with another anti-tumour agent,optionally selected from one listed herein above.

Herein, where the term “combination” is used it is to be understood thatthis refers to simultaneous, separate or sequential administration. Inone aspect of the invention “combination” refers to simultaneousadministration. In another aspect of the invention “combination” refersto separate administration. In a further aspect of the invention“combination” refers to sequential administration. Where theadministration is sequential or separate, the delay in administering thesecond component should not be such as to lose the beneficial effect ofthe combination.

According to a further aspect of the invention there is provided apharmaceutical composition which comprises a compound of the invention,or a pharmaceutically acceptable salt thereof, in combination with ananti-tumour agent (optionally selected from one listed herein above), inassociation with a pharmaceutically acceptable diluent or carrier.

In another embodiment, the invention relates to a therapeuticcombination comprising a compound as defined herein and another agentused to treat AML leukeamia e.g., cytarabine, FLT3 inhibitors, BCL2inhibitors or IDH1/2 inhibitors. Suitably, the agent used to treat AMLleukaemia is a BCL2 inhibitor, such as venetoclax.

EXAMPLES

The following abbreviations have been used in the Examples:

AlBN—Azobisisobutyronitrile

DBU—1,8-Diazabicyclo[5.4.0]undec-7-ene

DCE—Dichloroethane DCM—Dichloromethan

DIBAL—Diisobutylaluminium hydrideDIPEA—N-ethyl-N-isopropyl-propan-2-amine

DMAP—4-Dimethylaminopyridine DMF—Dimethylformamide

DMSO—Dimethyl sulfoxideDPPA—Diphenylphosphoryl azideHATU—[dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylene]-dimethyl-ammonium;hexafluorophosphateHPLC—High performance liquid chromatography

IPA—Isopropanol

LCMS—Liquid chromatograph mass spectrometry

NBS—N-Bromosuccinimide

NMP—N-Methyl-2-pyrrolidonePhase sep cartridge—Telos phase separator 6 mLRBF— Round bottomed flaskRM—Reaction mixture

RT—Retention Time

STAB—Sodium triacetoxyborohydrideT3P—Propylphosphonic anhydrideTBAF—Tetra-n-butylammonium fluoride

TEA—Triethylamine

TFA—Trifluoroacetic acidTFAA—Trifluoroacetic anhydride

THF—Tetrahydrofuran

The following methodologies have been used in the Examples:LCMS method A refers to low pH analysis using a mobile phase consistingof 0.1% formic acid in a gradient of 5-100% MeCN in water over 1.2 minat a flow rate of 1.2 mL/min. The stationary phase consisted of aKinetex Core-Shell C18, 2.1 mm×50 mm, 5 μm. The experiment was run at40° C.LCMS Method B refers to high pH analysis using a mobile phase consistingof 2 mM ammonium bicarbonate, buffered to pH10 in a gradient of 5-100%MeCN in water over 2.1 min at a flow rate of 1.0 mL/min. The stationaryphase consisted of a Phenomenex Gemini-NX C18, 2.0×50 mm, 3 μm. Theexperiment was run at 40° C.LCMS Method C refers to high pH analysis using a mobile phase consistingof 2 mM ammonium bicarbonate, buffered to pH10 in a gradient of 5-100%MeCN in water over 5.8 min at a flow rate of 0.6 mL/min. The stationaryphase consisted of a Waters UPLC® BEH™ C18, 2.1×100 mm, 1.7 μm. Theexperiment was run at 40° C.LCMS Method D refers to high pH analysis using a mobile phase consistingof 2 mM ammonium bicarbonate, buffered to pH10 in a gradient of 5-100%MeCN in water over 5.9 min at a flow rate of 0.6 mL/min. The stationaryphase consisted of a Phenomenex Gemini-NX C18, 2.0×100 mm, 3 μm. Theexperiment was run at 40° C.LCMS method E refers to low pH analysis using a mobile phase consistingof 0.1% formic acid in a gradient of 5-100% MeCN in water over 5.3 minat a flow rate of 0.6 mL/min. The stationary phase consisted of aPhenomenex Kinetix-XB C18, 2.1 mm×100 mm, 1.7 μm. The experiment was runat 40° C.LCMS method F refers to high pH analysis using a mobile phase consistingof 2 mM ammonium bicarbonate, buffered to pH10 in a gradient of 5-100%MeCN in water over 0.75 min at a flow rate of 1.0 mL/min. The stationaryphase consisted of a Waters UPLC® BEH™ C18, 2.1×100 mm, 1.7 μm. Theexperiment was run at 40° C.Method G refers to low pH analysis using a mobile phase consisting of0.1% Formic acid in water (pH=2.70) in a gradient of 3-100% of 0.1%formic acid in water:acetonitrile (10:90) over 3.00 min at a flow rateof 0.8 mL/min. The stationary phase consisted of C18, 50*2.1 mm, 1.6 μmcolumn. The experiment was run at 35° C.Method H refers to a high pH analysis using a mobile phase consisting of5 mM ammonium bicarbonate, (pH 7.35) in a gradient of MeCN in water over3.0 min at a flow rate of 0.5 mL/min. The stationary phase consisted ofC18, 50*2.1 mm, 2.5 μm. The experiment was run at 35° C.Method I refers to a high pH analysis using a mobile phase consisting of5 mM ammonium bicarbonate, (pH 7.35) in a gradient of MeCN in water over3.0 min at a flow rate of 0.5 mL/min. The stationary phase consisted ofC18, 50*2.1 mm, 2.5 μm. The experiment was run at 35° C.Method J refers to high pH analysis using a mobile phase consisting of 2mM ammonium bicarbonate, buffered to pH10 in a gradient of 1-100% MeCNover 1.35 min at a flow rate of 1 mL/min. The stationary phase consistedof a Waters UPLC® BEH™ C18 2.1×30 mm, 1.7 μm. The experiment was run at40° C.Method K refers to a Low pH analysis using a mobile phase consisting of0.1% Formic acid in water in a gradient of 5-100% of 0.1% formic acid inwater: 0.1% formic acid in acetonitrile over 5.4 min at a flow rate of0.6 mL/min. The stationary phase consisted of Phenomenex KinetexCore-Shell C8 50×2.1 mm, 2.6 um (protected by a “security Guard” column.The experiment was run at 40° C.Method L refers to a Low pH analysis using a mobile phase consisting of0.1% Formic acid in water in a gradient of 5-100% of 0.1% formic acid inwater: 0.1% formic acid in acetonitrile over 1.1 min at a flow rate of0.9 mL/min. The stationary phase consisted of Waters UPLC® BEH™ C182.1×50 mm, 1.7 μm. The experiment was run at 40° C.Method M refers to a Low pH analysis using a mobile phase consisting of0.1% Formic acid in water in a gradient of 5-100% of 0.1% formic acid inwater: 0.1% formic acid in acetonitrile over 2.25 min at a flow rate of1.2 mL/min. The stationary phase consisted of Phenomenex KinetexCore-Shell C8 50×2.1 mm, 2.6 um. The experiment was run at 40° C.LC04_ABF3 refers to high pH analysis using a mobile phase consisting of5 mM ammonium bicarbonate, buffered to pH10 in a gradient of 50-100%acetonitrile in water over 2.70 min at a flow rate of 1.0 mL/min. Thestationary phase consisted of a Waters UPLC® C18 4.6×50 mm, 3.5 μm. Theexperiment was run at 30° C.LC04_ABR2 refers to high pH analysis using a mobile phase consisting of5 mM ammonium bicarbonate, buffered to pH10 in a gradient of 10-100%acetonitrile in water over 9.0 min at a flow rate of 1.0 mL/min. Thestationary phase consisted of a Waters UPLC® BEH™ 018 4.6×150 mm, 3.5μm. The experiment was run at 30° C.LC03_ABR2 refers to high pH analysis using a mobile phase consisting of5 mM ammonium bicarbonate, buffered to pH 10 in a gradient of 3-100%Acetonitrile in water over 3.0 min at a flow rate of 0.5 mL/min. Thestationary phase consisted of a Waters UPLC® BEH™ C18 2.1×50 mm, 2.5 μm.The experiment was run at 30° C.UC02_FAR1 refers to low pH analysis using a mobile phase consisting of0.1% Formic acid in water (pH=2.70) in a gradient of 3-100% of 0.1%formic acid in water:acetonitrile (10:90) in water over 3.00 min at aflow rate of 0.8 mL/min. The stationary phase consisted of a WatersUPLC® BEH™ C18 2.1×50 mm, 2.5 μm. The experiment was run at 30° C.The following preparative HPLC methodologies have used in the Examples:Preparative Method A refers to low pH purification using a mobile phaseconsisting of 0.1% Formic acid in a gradient of 10-95% MeCN in waterover 14.4 min at a flow rate of 40 mL/min. The stationary phaseconsisted of a Waters Sunfire C18, 30×100 mm, 10 μm.Preparative Method B refers to high pH purification using a mobile phaseconsisting of 0.2% ammonium hydroxide in a gradient of 30-95% MeCN inwater over 10 min at a flow rate of 40 mL/min. The stationary phaseconsisted of a Waters XBridge™ C18 OBD™, 30×100 mm, 10 μm.

Intermediate 1: 4—Oxopyrido[1,2-a]pyrimidine-2-carboxylic acid

Methyl 4-oxopyrido[1,2-a]pyrimidine-2-carboxylate [Tetrahedron (2014),70(17), 2761-2765](3.94 g, 19.3 mmol) was dissolved in hydrogen chloridesolution (8M, 7.5 mL) at room temperature (An exotherm was noted onaddition) and the mixture was heated at reflux at for 2 h. The mixturewas cooled to room temperature and the precipitate was collected byfiltration and dried under vacuum to give the title compound (3.00 g,81%) as a white solid.Method A: LC-MS (electrospray): m/z=191.1 (M+H)⁺, RT=0.32 min

Example 1:N-({2-[(4,4-dimethylpiperidin-1-yl)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

Step 1: 2-(4,4-dimethylpiperidine-1-carbonyl)-1H-indole-6-carbonitrile

HATU (809 mg, 2.13 mmol) was added to a mixture of6-cyano-1H-indole-2-carboxylic acid (330 mg, 1.77 mmol) and DIPEA (1.5mL, 8.86 mmol) in DMF (26 mL), the mixture was stirred at ambienttemperature for 5 mins, 4,4-dimethylpiperidine hydrochloride (292 mg,1.95 mmol) was then added, and the mixture was stirred at ambienttemperature for 1 h. The mixture was extracted with EtOAc and H₂O, thelayers were separated, the mixture was extracted with EtOAc (3×10 mL),the organic layer was washed with brine, dried over MgSO₄ andconcentrated. Purification by Basic reverse phase HPLC gave the titlecompound (100 mg, 20%) as a yellow solid.Method A: LC-MS (electrospray): m/z=281.95 (M+H)⁺, RT=1.20 min

Step 2: [2-[(4,4-dimethyl-1-piperidyl)methyl]-1H-indol-6-yl]methanamine

Lithium aluminium hydride (2M in THF, 0.22 mL, 0.44 mmol) was added to asolution of2-(4,4-dimethylpiperidine-1-carbonyl)-1H-indole-6-carbonitrile (100 mg,0.355 mmol) in THF-Anhydrous (2 mL) at 0° C. The mixture was stirred at0° C., then was warmed to room temperature and stirred for 1 h. Furtherlithium aluminium hydride (2M in THF, 0.22 mL, 0.44 mmol) was added, andthe mixture was stirred at ambient temperature for 67 h. The reactionwas cooled to 0° C. and treated dropwise with H₂O (2 mL), NaOH (1M, 2mL) and H₂O (6 mL). The mixture was stirred for 10 minutes, filtered,and the filter cake washed with THF. The filtrate was concentrated andpurified by acidic reverse phase chromatography to give the titlecompound (86 mg, 89%) as a yellow solid.

Method A: LC-MS (electrospray): m/z=272.1 (M+H)⁺, RT=0.31 min

Step 3:N-({2-[(4,4-dimethylpiperidin-1-yl)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

HATU (80 mg, 0.210 mmol) was added to a mixture of4-oxopyrido[1,2-a]pyrimidine-2-carboxylic acid Intermediate 1 (60%, 61mg, 0.19 mmol) and DIPEA (0.15 mL, 0.88 mmol) in DMF (2.6 mL), themixture was stirred at ambient temperature for 5 minutes,[2-[(4,4-dimethyl-1-piperidyl)methyl]-1H-indol-6-yl]methanamine (48 mg,0.18 mmol) was then added, and the mixture was stirred at ambienttemperature for 1 h. Further HATU (45 mg) was added and the stir wascontinued for 2 h. The mixture was portioned between EtOAc and H₂O, thelayers were separated, and the mixture was extracted with EtOAc (3×10mL). The organic layer was washed with brine, dried over MgSO₄ andconcentrated under vacuum. The crude material was purified bypreparative HPLC (Method B) to give the title compound (4.0 mg, 5.1%) asa white solid.Method B: LC-MS (electrospray): m/z=444.3 (M+H)⁺, RT=4.59 min

Example 2:N-[(2-{[(cyclobutylmethyl)amino]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

Step 1: 3-amino-4-(3,3-diethoxyprop-1-yn-1-yl)benzonitrile

To a solution of 3-amino-4-iodobenzonitrile (8.00 g, 32.8 mmol) inTHF-Anhydrous (40 mL) and triethylamine (80 mL, 0.574 mol) was addedPd₂(PPh₃)₂Cl₂ (230 mg, 0.328 mmol) and triphenylphosphine (172 mg, 0.656mmol) at ambient temperature. The solution was de-gassed by bubblingnitrogen into the solution for 20 minutes. Then copper (1) iodide (125mg, 0.66 mmol) and 3,3-diethoxyprop-1-yne (5.04 g, 39.3 mmol) were addedsequentially and the reaction was stirred under nitrogen atmosphere for18 hours. The precipitate (triethylamine hydrochloride) was collected byfiltration and washed with EtOAc (˜20 mL). The filtrate was concentratedat reduced pressure and the residue was purified by chromatography onSiO₂ [Biotage KP-Sil 100 g, eluting with 0-50% EtOAc in heptane]. Theproduct containing fractions were combined and concentrated in vacuo toafford the title compound (8.19 g, Quant) as an orange oil.Method B: LC-MS (electrospray): m/z=262.3 (M+H)⁺, RT=1.65 min.

Step 2: 2-(diethoxymethyl)-1H-indole-6-carbonitrile

To a stirred solution of 3-amino-4-(3,3-diethoxyprop-1-ynyl)benzonitrile(8.00 g, 31.1 mmol) in NMP (99 mL) was added potassium tert-butoxide(6.98 g, 62.2 mmol) at 0° C. (the colour of the solution turned fromorange to dark red). After warming to RT, the solution was stirred atambient temperature for 16 hours. Saturated aqueous ammonium chloridesolution (25 mL) was added and the resulting mixture was partitionedbetween EtOAc (250 mL) and water (250 mL). The layers were separated andthe organic layer washed twice more with water (2×200 mL). The organiclayer was dried over sodium sulfate, filtered and concentrated in vacuoto give a brown oil. The first aqueous layer was re-extracted with EtOAc(200 mL) and the layers separated. The organic layer was washed twicewith water (2×200 mL). The organic layer was dried over sodium sulfate,filtered and concentrated in vacuo to give an orange oil. The crudematerial was purified by chromatography on SiO₂ [BIOTAGE KP-Sil 100 g,eluting with 0-50% EtOAc in heptane]. The product containing fractionswere combined and concentrated in vacuo. The residue (yellow solid) wasrecrystallised from EtOAc/heptane to afford the title compound (5.86 g,24.0 mmol, 77%) as colourless crystalline solid.Method B: LC-MS (electrospray): m/z=262.3 (M+H)⁺, RT=1.69 min.

Step 3: [2-(diethoxymethyl)-1H-indol-6-yl]methanamine

To a degassed solution of 2-(diethoxymethyl)-1H-indole-6-carbonitrile(5.8 g, 24 mmol) in ethanol (70 mL) was added ammonia in MeOH (7M, 20mL, 0.14 mmol) and the reaction was degassed and backfilled withnitrogen 3 times. Raney nickel (assumed 50%, about 5.4 g, 0.1 mmoL) wasadded and the reaction evacuated and backfilled with nitrogen 3 times.The flask was evacuated one final time and put under a hydrogenatmosphere and stirred at ambient temperature for 3 hours. More Raneynickel (about 2.7 g) was added and the reaction evacuated and placedunder a hydrogen atmosphere and stirred at ambient temperature for 16hours. The catalyst was removed by filtration (through Kieselguhr) andwashed with methanol (50 mL). The filtrate was concentrated underreduced pressure to afford the title compound (5.96 g, 100%) as acolourless oil which crystallised upon standing.Method C: LC-MS (electrospray): m/z=247.3 (M−H)⁻, RT=2.74 min.

Step 4:N-[(2-formyl-1H-indol-6-yl)methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide

To a stirred solution of 4-oxopyrido[1,2-a]pyrimidine-2-carboxylic acid(455 mg, 2.39 mmol) (Intermediate 1) and DIPEA (1.0 mL, 5.98 mmol) inDMF (10 mL) was added HATU (910 mg, 2.39 mmol). A colour change wasobserved from colourless to green and a suspension formed. After afurther 30 minutes of stirring at ambient temperature, a solution of[2-(diethoxymethyl)-1H-indol-6-yl]methanamine (500 mg, 1.99 mmol) in DMF(5 mL) was added dropwise to the reaction. A colour change of green tored was observed and the reaction became homogeneous and was stirred atambient temperature overnight.The mixture was partitioned between EtOAc (100 mL) and sat. NaHCO₃solution (50 mL). The organic layer was separated, washed with water (80mL) and brine (20 mL), dried (Na₂SO₄), filtered and concentrated atreduced pressure to give a viscous red oil.The crude product was dissolved in THE (10 mL), water (1 mL) and aceticacid (0.5 mL) were added and the mixture was stirred at ambienttemperature for 2 hours.The THF was removed in vacuo and water (10 mL) was added to theresulting mixture causing further solid to precipitate out. The brownsolid was collected by washed with water (2×5 mL) then ether (3×5 mL)and dried under vacuum to give the title compound (520 mg, 75%) as abrown solid.Method C: LC-MS (electrospray): m/z=347.2 (M+H)⁺, RT=2.37 min.

Step 5:N-[[2-[(Cyclobutylmethylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide

A pressure vial was charged withN-[(2-formyl-1H-indol-6-yl)methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide(185 mg, 0.53 mmol), DCE (5 mL) and 1-cyclobutylmethanamine (0.13 mL,1.0 mmol) at ambient temperature. The vial was sealed and the mixturewas stirred at 65° C. for 2 hours. After cooling to RT, sodiumtriacetoxyborohydride (340 mg, 1.85 mmol) was added and the mixture washeated to 65° C. for 2 hours.The mixture was partitioned between EtOAc (40 mL) and sat. sodiumbicarbonate solution (30 mL). The organic layer was separated, washedwith brine (20 mL), dried (Na₂SO₄), filtered and concentrated at reducedpressure. The residue (pale yellow oil) was purified by reverse phasechromatography (basic method, SNAP ULTRA 30 g Cartridge, eluting withMeCN+0.1% NH₃/H₂O+0.1% NH₃, 10 to 90%). The fractions containing desiredproduct were freeze dried overnight to give the title compound (85 mg,38%) as an off-white solid.Method C: LC-MS (electrospray): m/z=416.4 (M+H)⁺, RT=3.14 min.

Example 6:N-[[2-[[(1-methylcyclopropyl)methylamino]methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide

(1-methylcyclopropyl)methanamine hydrochloride (70 mg, 0.577 mmol) wasadded to a solution ofN-[(2-formyl-1H-indol-6-yl)methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide(100 mg, 0.289 mmol) in DCE (7 mL) in a pressure vial, and the RM wasstirred at 60° C. for 3 h. (1-methylcyclopropyl)methanaminehydrochloride (70 mg, 0.577 mmol) was added, along withN-ethyl-N-isopropyl-propan-2-amine (0.30 mL, 1.73 mmol) and the reactionwas stirred at 60° C. for 1 h. The mixture was cooled to roomtemperature and added drop-wise over 5 min to a solution of NaBH₄ (11mg, 0.289 mmol) in Ethanol (2.5 mL). The mixture was stirred at ambienttemperature overnight. NaBH₄ (11 mg, 0.289 mmol) in Ethanol (2.5 mL) wasadded dropwise, and the reaction stirred at ambient temperature for afurther 1 h. The mixture was quenched with water (30 mL), extracted withDCM (3×40 mL), passed through a Telos phase separator and concentratedin vacuo. The residue was purified by preparative HPLC (Method B) andthe product containing fractions combined, concentrated in vacuo andfreeze dried overnight to afford the title compound (70 mg, 59% as apale yellow solid.Method C: LC-MS (electrospray): m/z=416.5 (M+H)⁺, RT=3.16 minThe compounds in Table 1 were prepared in the same manner as Example 2and 3 using commercial amines or described intermediates.

TABLE 1 Com- LCMS pound LCMS Retention Mass No Name Structure methodtime Ion 3 N-[[2-[[(3,3- difluorocyclo- butyl)methyl- amino]methyl]-1H-indol-6- yl]methyl]-4- oxo-pyrido[1,2- a]pyrimidine-2- carboxamide

C 2.98 452.4 4 N-[[2-[[(1- hydroxycyclo- butyl)methyl- amino]methyl]-1H- indol-6- yl]methyl]-4- oxo-pyrido[1,2- a]pyrimidine-2- carboxamide

C 2.54 432.5 5 N-[[2-[[(1- fluorocyclobutyl) methylamino] methyl]-1H-indol-6- yl]methyl]-4- oxo-pyrido[1,2- a]pyrimidine-2- carboxamide

C 3.01 434.4 7 N-[[2-(2- azabicyclo[2.1.1] hexan-2- ylmethyl)-1H-indol-6- yl]methyl]-4- oxo-pyrido[1,2- a]pyrimidine-2- carboxamide

C 2.96 414.4 8 N-[[2-(3- azabicyclo[3.1.1] heptanean- 3-ylmethyl)-1H-indol-6- yl]methyl]-4- oxo-pyrido[1,2- a]pyrimidine-2- carboxamide

C 3.67 428.4 9 N-[[2-[[2- (hydroxymethyl) pyrrolidin-1- yl]methyl]-1H-indol-6- yl]methyl]-4- oxo-pyrido[1,2- a]pyrimidine-2- carboxamide

C 2.66 432.4 10 N-[[2- (morpholino- methyl)-1H-indol- 6-yl]methyl]-4-oxo-pyrido[1,2- a]pyrimidine-2- carboxamide

C 2.52 418.3 11 N-[[2-[(1- adamantylamino) methyl]-1H- indol-6-yl]methyl]-4- oxo-pyrido[1,2- a]pyrimidine-2- carboxamide

C 4.02 482.5 12 4-oxo-N-[[2-(1- piperidylmethyl)- 1H-indol-6- yl]methyl]pyrido[1,2- a]pyrimidine-2- carboxamide

C 3.29 416.4 13 N-[[2-[(4- fluoro-1- piperidyl)methyl]- 1H-indol-6-yl]methyl]-4- oxo-pyrido[1,2- a]pyrimidine-2- carboxamide

C 3.00 434.4 14 4-oxo-N-[[2- [[[rac- (1S,2S,4S)-7- oxabicyclo[2.2.1]heptane-5- en-2- yl]methylamino] methyl]-1H- indol-6- yl]methyl]pyrido[1,2- a]pyrimidine-2- carboxamide

C 2.62 456.5

15 N-[[2-[[(1- hydroxycyclo- pentyl)methyl- amino]methyl]- 1H-indol-6-yl]methyl]-4- oxo-pyrido[1,2- a]pyrimidine-2- carboxamide

C 2.74 446.4 16 4-oxo-N-[[2- [[[rac- (1S,2R,4S)-7- oxabicyclo[2.2.1]heptane-5- en-2- yl]methylamino] methyl]-1H- indol-6- yl]methyl]pyrido[1,2- a]pyrimidine-2- carboxamide

C 2.57 456.4 17 N-[[2-[(1- bicyclo[1.1.1] pentanylamino) methyl]-1H-indol-6- yl]methyl]-4- oxo-pyrido[1,2- a]pyrimidine-2- carboxamide

C 3.06 414.4 18 N-[[2- [(cyclobutyl- amino) methyl]-1H- indol-6-yl]methyl]-4- oxo-pyrido[1,2- a]pyrimidine-2- carboxamide

C 2.90 402.4 19 N-({2- [({bicyclo[2.2.1] heptanean-2- yl}amino) methyl]-1H-indol-6- yl}methyl)-4- oxo-4H- pyrido[1,2- a]pyrimidine-2-carboxamide

C 3.52 442.4 20 N-[[2- [(cyclopropyl- amino)methyl]- 1H-indol-6-yl]methyl]-4- oxo-pyrido[1,2- a]pyrimidine-2- carboxamide

C 2.69 388.4 21 N-[[2-(2- azabicyclo[2.2.2] octan-2- ylmethyl)-1H-indol-6- yl]methyl]-4- oxo-pyrido[1,2- a]pyrimidine-2- carboxamide

C 3.69 442.4 22 N-[[2-[[(2,2- difluorocyclopro- pyl)methylamino]methyl]-1H- indol-6- yl]methyl]-4- oxo-pyrido[1,2- a]pyrimidine-2-carboxamide

C 2.82 438.3 23 N-[(2-{[({3- fluorobicyclo [1.1.1]pentan-1-yl}methyl)amino] methyl}-1H- indol-6- yl)methyl]-4- oxo-4H- pyrido[1,2-a]pyrimidine-2- carboxamide

C 3.01 446.4 24 N-[[2- [(cyclohexyl- methylamino) methyl]-1H- indol-6-yl]methyl]-4- oxo-pyrido[1,2- a]pyrimidine-2- carboxamide

C 3.68 444.5 25 N-[[2-[[(1- hydroxycyclo- hexyl)methyl- amino]methyl]-1H- indol-6- yl]methyl]-4- oxo-pyrido[1,2- a]pyrimidine-2-carboxamide

C 2.98 460.5 26 N-[[2- [(cyclopentyl- amino)methyl]- 1H-indol-6-yl]methyl]-4- oxo-pyrido[1,2- a]pyrimidine-2- carboxamide

C 3.10 416.5 27 N-[[2- [(cyclopentyl- methylamino) methyl]- 1H-indol-6-yl]methyl]-4- oxo-pyrido[1,2- a]pyrimidine-2- carboxamide

C 3.40 430.5 28 N-[[2-[[(1- methoxycyclo- butyl)methyl- amino]methyl]-1H- indol-6- yl]methyl]-4- oxo-pyrido[1,2- a]pyrimidine-2-carboxamide

C 2.91 446.5 29 N-[[2- [(isobutylamino) methyl]-1H- indol-6-yl]methyl]-4- oxo-pyrido[1,2- a]pyrimidine-2- carboxamide

C 3.06 404.5 30 N-[[2- [(cyclohexyl- amino)methyl]- 1H-indol-6-yl]methyl]-4- oxo-pyrido[1,2- a]pyrimidine-2- carboxamide

C 3.29 430.5 31 N-[[2- [(cyclopropyl- methylamino) methyl]- 1H-indol-6-yl]methyl]-4- oxo-pyrido[1,2- a]pyrimidine-2- carboxamide

C 2.81 402.5 32 4-oxo-N-[[2- [(prop-2- ynylamino) methyl]- 1H-indol-6-yl]methyl] pyrido[1,2- a]pyrimidine-2- carboxamide

C 2.51 386.3 33 N-[[2-[(oxetan- 2- ylmethylamino) methyl]-1H- indol-6-yl]methyl]-4- oxo-pyrido[1,2- a]pyrimidine-2- carboxamide

C 2.33 418.5 34 N-[[2-[(2,2- dimethylpropyl amino)methyl]- 1H-indol-6-yl]methyl]-4- oxo-pyrido[1,2- a]pyrimidine-2- carboxamide

C 3.37 418.5 35 N-[[2-[(1- bicyclo[1.1.1] pentanylmethyl- amino)methyl]-1H-indol-6- yl]methyl]-4- oxo-pyrido[1,2- a]pyrimidine-2- carboxamide

C 3.23 428.4 36 N-{[2- ({[(1S,2S)-2- hydroxycyclo- pentyl]amino}methyl)-1H- indol-6- yl]methyl}-4- oxo-4H- pyrido[1,2- a]pyrimidine-2-carboxamide

D 3.15 432.3 37 N-{[2- ({[(1R,2R)-2- hydroxycyclo- pentyl]amino}methyl)-1H- indol-6- yl]methyl}-4- oxo-4H- pyrido[1,2- a]pyrimidine-2-carboxamide

D 3.15 432.3 38 N-{[2- ({[(1S,2R)-2- hydroxycyclo- pentyl]amino}methyl)-1H- indol-6- yl]methyl}-4- oxo-4H- pyrido[1,2- a]pyrimidine-2-carboxamide

D 3.39 432.3 39 N-{[2- ({[(1R,2S)-2- hydroxycyclo- pentyl]amino}methyl)-1H- indol-6- yl]methyl}-4- oxo-4H- pyrido[1,2- a]pyrimidine-2-carboxamide

D 3.38 432.3 40 N-[[2- [(cyclopropyl- methylamino) methyl]-5-fluoro-1H-indol-6- yl]methyl]-4- oxo-pyrido[1,2- a]pyrimidine-2- carboxamide

C 2.99 420.5 41 N-[[2- [(cyclobutyl- methylamino) methyl]-5- fluoro-1H-indol-6- yl]methyl]-4- oxo-pyrido[1,2- a]pyrimidine-2- carboxamide

C 3.28 434.5 67 N-[[2-(2- azaspiro[3.3] heptanean-2- ylmethyl)-1H-indol-6- yl]methyl]-4- oxo-pyrido[1,2- a]pyrimidine-2- carboxamide

C 3.26 428.4 68 N-[[2- [(benzylamino) methyl]-1H- indol-6- yl]methyl]-4-oxo-pyrido[1,2- a]pyrimidine-2- carboxamide

C 3.16 438.5 69 N-[[2-(3- azabicyclo[3.1.0] hexan-3- ylmethyl)-1H-indol-6- yl]methyl]-4- oxo-pyrido[1,2- a]pyrimidine-2- carboxamide

C 3.30 414.4 73 N-[(2-{[(but-2- yn-1- yl)amino] methyl}- 1H-indol-6-yl)methyl]-4- oxo-4H- pyrido[1,2- a]pyrimidine-2- carboxamide

C 2.74 400.474 74 N-[(2-{[(3- cyclopropyl- prop-2-yn-1- yl)amino]methyl}- 1H-indol-6- yl)methyl]-4- oxo-4H- pyrido[1,2- a]pyrimidine-2-carboxamide

C 3.03 426.4 75 N-({2- [({bicyclo[3.1.0] hexan-6- yl}amino) methyl]-1H-indol-6- yl}methyl)-4- oxo-4H- pyrido[1,2- a]pyrimidine-2-carboxamide

C 3.26 428.5 76 N-[(2- {[({bicyclo[2.1.1] hexan-1- yl}methyl)amino]methyl}-1H- indol-6- yl)methyl]-4- oxo-4H- pyrido[1,2- a]pyrimidine-2-carboxamide

E 1.87 442.4 77 N-[(2-{[({3- methylbicyclo [1.1.1]pentan- 1-yl}methyl)amino] methyl}-1H- indol-6- yl)methyl]-4- oxo-4H- pyrido[1,2-a]pyrimidine-2- carboxamide

C 3.52 442.6 78 N-({2-[(3- methylazetidin- 1-yl)methyl]- 1H-indol-6-yl}methyl)-4- oxo-4H- pyrido[1,2- a]pyrimidine-2- carboxamide

C 2.94 402.4 79 N-({2-[(3- fluoroazetidin- 1-yl)methyl]- 1H-indol-6-yl}methyl)-4- oxo-4H- pyrido[1,2- a]pyrimidine-2- carboxamide

C 2.63 406.4 80 N-({2- [(azetidin-1- yl)methyl]-1H- indol-6-yl}methyl)-4- oxo-4H- pyrido[1,2- a]pyrimidine-2- carboxamide

C 2.73 388.5 81 N-{[2-({2- azaspiro[3.4] octan-2- yl}methyl)-1H-indol-6- yl]methyl}-4- oxo-4H- pyrido[1,2- a]pyrimidine-2- carboxamide

C 3.53 442.5 82 N-({2-[(3- hydroxyazetidin- 1-yl)methyl]- 1H-indol-6-yl}methyl)-4- oxo-4H- pyrido[1,2- a]pyrimidine-2- carboxamide

C 2.10 404.4 83 N-({2-[(3,3- dimethylazetidin- 1-yl)methyl]- 1H-indol-6-yl}methyl)-4- oxo-4H- pyrido[1,2- a]pyrimidine-2- carboxamide

C 3.20 416.4 84 4-oxo-N-[(2- {[3-(2,2,2- trifluoroethoxy) azetidin-1-yl]methyl}-1H- indol-6- yl)methyl]-4H- pyrido[1,2- a]pyrimidine-2-carboxamide

C 3.16 486.5 85 N-[(2-{[3- (difluoromethyl) azetidin-1- yl]methyl}-1H-indol-6- yl)methyl]-4- oxo-4H- pyrido[1,2- a]pyrimidine-2- carboxamide

C 2.92 438.4 86 N-({2-[(3- methoxyazetidin- 1-yl)methyl]- 1H-indol-6-yl}methyl)-4- oxo-4H- pyrido[1,2- a]pyrimidine-2- carboxamide

C 2.58 418.5 87 N-[(2-{[3-(tert- butoxy)azetidin- 1-yl]methyl}-1H-indol-6- yl)methyl]-4- oxo-4H- pyrido[1,2- a]pyrimidine-2-carboxamide

C 3.18 460.6 88 4-oxo-N-[(2- {[3- (trifluoromethyl) azetidin-1-yl]methyl}-1H- indol-6- yl)methyl]-4H- pyrido[1,2- a]pyrimidine-2-carboxamide

C 3.11 456.4 89 N-({2-[(3- ethoxyazetidin- 1-yl)methyl]- 1H-indol-6-yl}methyl)-4- oxo-4H- pyrido[1,2- a]pyrimidine-2- carboxamide

C 2.80 432.5 90 N-{[2-({2- azaspiro[3.5] nonan-2- yl}methyl)-1H-indol-6- yl]methyl}-4- oxo-4H- pyrido[1,2- a]pyrimidine-2- carboxamide

C 3.77 456.5 91 N-({2-[(2- methylazetidin- 1-yl)methyl]- 1H-indol-6-yl}methyl)-4- oxo-4H- pyrido[1,2- a]pyrimidine-2- carboxamide

C 2.94 402.4 92 N-({2-[(3,3- dimethyl- pyrrolidin-1- yl)methyl]-1H-indol-6- yl}methyl)-4- oxo-4H- pyrido[1,2- a]pyrimidine-2- carboxamide

C 3.63 430.7 93 N-{[2-({6- fluoro-2- azaspiro[3.3] heptanean-2-yl}methyl)-1H- indol-6- yl]methyl}-4- oxo-4H- pyrido[1,2-a]pyrimidine-2- carboxamide

C 3.00 446.4 94 N-[2-({6,6- difluoro-2- azaspiro[3.3] heptanean-2-yl}methyl)-1H- indol-6- yl]methyl}-4- oxo-4H- pyrido[1,2-a]pyrimidine-2- carboxamide

C 3.10 464.595 95 N-({2-[(3- cyclobutyl- azetidin-1- yl)methyl]-1H-indol-6- yl}methyl)-4- oxo-4H- pyrido[1,2- a]pyrimidine-2- carboxamide

C 3.63 442.8 96 N-({2-[(3- cyclopropyl- azetidin-1- yl)methyl]-1H-indol-6- yl}methyl)-4- oxo-4H- pyrido[1,2- a]pyrimidine-2- carboxamide

C 3.31 429.1 97 N-({2-[(3-tert- butylazetidin- 1-yl)methyl]- 1H-indol-6-yl}methyl)-4- oxo-4H- pyrido[1,2- a]pyrimidine-2- carboxamide

E 1.94 444.5 98 N-[(2-{[(1-tert- butylcyclo- propyl)amino] methyl}-1H-indol-6- yl)methyl]-4- oxo-4H- pyrido[1,2- a]pyrimidine-2-carboxamide

C 4.19 444.6 99 N-{[2-({[(3- methylcyclo- butyl)methyl] amino}methyl)-1H- indol-6- yl]methyl}-4- oxo-4H- pyrido[1,2- a]pyrimidine-2-carboxamide

C 3.51 430.7 100 4-oxo-N-[(2- {[(2,3,3- trimethylbutan- 2-yl)amino]methyl}- 1H-indol-6- yl)methyl]-4H- pyrido[1,2- a]pyrimidine-2-carboxamide

C 4.21 446.8 101 N-[(2- {[({imidazo[1,2- a]pyridin-2- yl}methyl)amino]methyl}-1H- indol-6- yl)methyl]-4- oxo-4H- pyrido[1,2- a]pyrimidine-2-carboxamide

C 2.55 478.5 102 N-({2-[(3,3- diethylazetidin- 1-yl)methyl]- 1H-indol-6-yl}methyl)-4- oxo-4H- pyrido[1,2- a]pyrimidine-2- carboxamide

E 1.92 444.5 103 4-oxo-N-[(2- {[(pent-3-yn-1- yl)amino] methyl}-1H-indol-6- yl)methyl]-4H- pyrido[1,2- a]pyrimidine-2- carboxamide

C 2.91 414.5 104 N-{[2-({6- azaspiro[3.4] octan-6- yl}methyl)-1H-indol-6- yl]methyl}-4- oxo-4H- pyrido[1,2- a]pyrimidine-2- carboxamide

C 4.01 442.7 105 N-({2-[(2,2- dimethyl- pyrrolidin-1- yl)methyl]-1H-indol-6- yl}methyl)-4- oxo-4H- pyrido[1,2- a]pyrimidine-2- carboxamide

C 3.66 430.6 106 N-{[2- ({octahydrocy- clopenta[c]pyrrol- 2-yl}methyl)-1H-indol-6- yl]methyl}-4- oxo-4H- pyrido[1,2- a]pyrimidine-2-carboxamide

C 3.69 442.8 107 N-{[2-({5- azaspiro[2.4] heptanean-5- yl}methyl)-1H-indol-6- yl]methyl}-4- oxo-4H- pyrido[1,2- a]pyrimidine-2- carboxamide

C 3.28 428.5 108 N-[(2-{[({3- methoxybicyclo [1.1.1]pentan- 1-yl}methyl)amino] methyl}-1H- indol-6- yl)methyl]-4- oxo-4H- pyrido[1,2-a]pyrimidine-2- carboxamide

C 2.96 458.6 109 4-oxo-N-[(2- {[({spiro[2.2] pentan-1- yl}methyl)amino]methyl}-1H- indol-6- yl)methyl]-4H- pyrido[1,2- a]pyrimidine-2-carboxamide

C 3.49 428.5 110 4-oxo-N-({2- [({spiro[2.3] hexan-1- yl}amino) methyl]-1H-indol-6- yl}methyl)-4H- pyrido[1,2- a]pyrimidine-2- carboxamide

C 3.35 428.5 111 N-[(2-{[({3- cyanobicyclo [1.1.1]pentan-1-yl}methyl)amino] methyl}-1H- indol-6- yl)methyl]-4- oxo-4H- pyrido[1,2-a]pyrimidine-2- carboxamide

C 2.89 453.5 112 N-{[2-({1-oxa- 6- azaspiro[3.4] octan-6- yl}methyl)-1H-indol-6- yl]methyl}-4- oxo-4H- pyrido[1,2- a]pyrimidine-2- carboxamide

C 2.65 444.5 113 N-{[2-({2- azaspiro[4.4] nonan-2- yl}methyl)-1H-indol-6- yl]methyl}-4- oxo-4H- pyrido[1,2- a]pyrimidine-2- carboxamide

C 3.88 456.5 139 N-[[2-(2- azabicyclo[2.2.1] heptanean- 2-ylmethyl)-1H-indol-6- yl]methyl]-4- oxo-pyrido[1,2- a]pyrimidine-2- carboxamide

C 3.39 428.4

Example 42:4-oxo-N-[[2-[(2,2,2-trifluoroethylamino)methyl]-1H-indol-6-yl]methyl]pyrido[1,2-a]pyrimidine-2-carboxamide

2,2,2-trifluoroethanamine (25 μL, 0.318 mmol) was added to a solution ofN-[(2-formyl-1H-indol-6-yl)methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamideExample 2 Step 4 (55 mg, 0.159 mmol) in DCE (4 mL) and1,1,1,3,3,3-Hexafluoro-2-propanol (2 mL) in a pressure vial, and themixture was stirred at 50° C. for 1 h. The mixture was cooled to roomtemperature and retreated with 2,2,2-trifluoroethanamine (25 μL, 0.318mmol) and left to stir at 50° C. for 2.5 h. The mixture was cooled toroom temperature and added dropwise over 5 mins to a solution of NaBH₄(18 mg, 0.476 mmol) in Ethanol (2 mL). The mixture was stirred atambient temperature overnight. The mixture was retreated with NaBH₄ (18mg, 0.476 mmol) and left to stir at ambient temperature for 1 h 15 mins.The mixture was quenched with water (30 mL) and extracted with DCM (3×40mL). The combined organic layers were passed through an Isolute phaseseparator and concentrated in vacuo. The crude material was purified bypreparative HPLC (Method B) to give the title compound (40.2 mg, 59%) asan off-white solid.Method C: LC-MS (electrospray): m/z=430.3 (M+H)⁺, RT=2.94 min

Example 70:N-[[2-[[cyclobutylmethyl(methyl)amino]methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide

To a solution ofN-[[2-[(cyclobutylmethylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide(200 mg, 0.481 mmol) in Chloroform (3 mL) and 2-Propanol (1 mL) wasadded N-ethyl-N-isopropyl-propan-2-amine (0.25 mL, 1.44 mmol) and methyliodide (30 μL, 0.481 mmol) at ambient temperature and the mixture wasstirred for 4 h. The mixture was concentrated under reduced pressure todryness. The residue was dissolved in MeOH (3 mL) and purified bypreparative HPLC (Method B). The product containing fraction werecombined and concentrated to dryness at reduced pressure. The residuewas dissolved in a 1:1 mixture of acetonitrile and water (4 mL) andlyophilsed to afford the title compound (65 mg, 31%) as pale yellowsolid.Method C: LC-MS (electrospray): m/z=430.4 (M+H)⁺, RT=3.62 min

Example 43:N-[(2-{[N-(cyclobutylmethyl)acetamido]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

To a solution ofN-[[2-[(cyclobutylmethylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamideExample 2 (150 mg, 0.350 mmol) and N-ethyl-N-isopropyl-propan-2-amine(0.18 mL, 1.05 mmol) in DCM (5 mL) was added acetic anhydride (36 μL,0.385 mmol) at ambient temperature and the mixture was stirred for 2 h.The mixture was concentrated at reduced pressure to dryness. The residuewas purified by preparative HPLC (Method B) to give the title compound(139 mg, 85.9%) as a white solid.Method E: LC-MS (electrospray): m/z=458.2 (M+H)⁺, RT=3.01 min

Example 44:4-oxo-N-{[2-(piperidin-2-yl)-1H-indol-6-yl]methyl}-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

Step 1: tert-butyl2-[2-(2-amino-4-cyano-phenyl)ethynyl]piperidine-1-carboxylate

To a solution of 3-amino-4-iodobenzonitrile (1.05 g, 4.30 mmol) inTHF-Anhydrous (5 mL) and triethylamine (10 mL, 71.7 mmol) was addedBis(triphenylphosphine)palladium(II) chloride (30 mg, 0.0430 mmol) andtriphenylphosphine (23 mg, 0.0861 mmol) at room temperature. Thesolution was de-gassed by bubbling nitrogen into the solution for 15minutes. Then copper (1) iodide (16 mg, 0.0861 mmol) and tert-butyl2-ethynylpiperidine-1-carboxylate (0.99 g, 4.73 mmol) were addedsequentially and the reaction was stirred under nitrogen atmosphere for4 h. The precipitate (triethylamine hydroiodide) was collected byfiltration and washed with EtOAc (˜20 mL). The filtrate was concentratedat reduced pressure and the residue was purified by chromatography onSiO₂ (eluting with 0-50% EtOAc in heptane). The product containingfractions were combined and concentrated in vacuo. The orange solid wastriturated with heptane. The resulting solid was collected byfiltration, washed with heptane (˜25 mL) and dried in the vacuum oven at45° C. for 2 h to afford the title compound (1.03 g, 70%) as a whitesolid.Method C: LC-MS (electrospray): m/z=651.5 (2M+H)⁺, RT=4.21 min

Step 2: tert-butyl 2-(6-cyano-1H-indol-2-yl)piperidine-1-carboxylate

To a stirred solution of tert-butyl2-[2-(2-amino-4-cyano-phenyl)ethynyl]piperidine-1-carboxylate (1.00 g,3.07 mmol) in NMP-Anhydrous (12 mL) was added potassium2-methylpropan-2-olate (0.69 g, 6.15 mmol) at 0° C. (the colour of thesolution turned from colourless to orange within seconds). After warmingto romm temperature for 16 h under a nitrogen atmosphere. Ammoniumchloride (sat., 5 mL) was added and the resulting mixture waspartitioned between EtOAc (100 mL) and water (80 mL). The organic layerwas separated, and the aqueous layer was extracted with EtOAc (50 mL).The combined organic layers were washed with water (2×50 mL) and brine(30 mL), dried (Na₂SO₄), filtered and concentrated at reduced pressure.The residue (brown solid) was purified by chromatography on SiO₂(eluting with 0-50% EtOAc in heptane). The product containing fractionswere combined and concentrated in vacuo. The residue (orange solid) wastriturated with heptane. The resulting solid was collected by vacuumfiltration, washed with heptane (10 mL) and dried in the vacuum oven at45° C. for 2 h to afford the title compound (875 mg, 87%) as whitesolid.Method C: LC-MS (electrospray): m/z=326.3 (M+H)⁺, RT=4.19 min

Step 3: tert-butyl2-[6-(aminomethyl)-1H-indol-2-yl]piperidine-1-carboxylate

The title compound (785 mg, 83%) was prepared from tert-butyl2-(6-cyano-1H-indol-2-yl)piperidine-1-carboxylate using the chemistrydescribed in Example 2 Step 3.Method E: LC-MS (electrospray): m/z=330.2 (M+H)⁺, RT=2.22 min.

Step 4: tert-butyl2-{6-[({4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl}formamido)methyl]-1H-indol-2-yl}piperidine-1-carboxylate

To a solution of 4-oxopyrido[1,2-a]pyrimidine-2-carboxylic acid (135 mg,0.711 mmol) (Intermediate 1), N-ethyl-N-isopropyl-propan-2-amine (0.11mL, 0.647 mmol) and tert-butyl2-[6-(aminomethyl)-1H-indol-2-yl]piperidine-1-carboxylate (213 mg, 0.647mmol) in DMF-Anhydrous (4 mL) was added HATU (246 mg, 0.647 mmol), themixture was stirred at ambient temperature for 2 h. The mixture waspartitioned between EtOAc (60 mL) and water (40 mL). The organic layerwas separated, washed with water (40 mL) and brine (20 mL), dried(Na₂SO₄), filtered and concentrated in vacuo to dryness. The residue waspurified by chromatography on SiO₂ (eluting with 0-100% EtOAc inheptane). The product containing fractions were combined andconcentrated in vacuo to afford the title compound (313 mg, 92%) asyellow oil.Method C: LC-MS (electrospray): m/z=502.4 (M+H)⁺, RT=3.89 min

Step 5:4-oxo-N-{[2-(piperidin-2-yl)-1H-indol-6-yl]methyl}-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

A solution of tert-butyl2-{6-[({4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl}formamido)methyl]-1H-indol-2-yl}piperidine-1-carboxylate(96%, 313 mg, 0.599 mmol) in 4M HCl in dioxane (4.5 mL) was stirred at40° C. for 2 h [the solution turned dark red and the production of gasceased]. The mixture was cooled to room temperature and concentrated atreduced pressure to dryness. The residue was dissolved in MeOH (3 mL)and by preparative HPLC (Method B). The product containing fractionswere combined and concentrated in vacuo to dryness. The residue wasdissolved in acetonitrile (2 mL) and water (2 mL) and lyophilsed toafford the title compound (120 mg, 49%) as pale yellow solid.Method C: LC-MS (electrospray): m/z=402.5 (M+H)⁺, RT=2.77 min

Example 45:N-[(2-{[(cyclobutylmethyl)amino]methyl}-3-fluoro-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

Step 1:N-[(3-fluoro-2-formyl-1H-indol-6-yl)methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide

To a solution ofN-[(2-formyl-1H-indol-6-yl)methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide(95%, 530 mg, 1.45 mmol) in NMP-Anhydrous (10 mL) was added1-Chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octanebis(tetrafluoroborate) (515 mg, 1.45 mmol) at room temperature and themixture was stirred for 3 days. The mixture was diluted with EtOAc (100mL), washed with water (50 mL) and brine (20 mL), dried (Na₂SO₄) andconcentrated at reduced pressure. The residue was purified bypreparative HPLC (Method B). The product containing fractions werecombined and concentrated to dryness to afford the title compound (97mg, 15%) as a beige solid.Method C: LC-MS (electrospray): m/z=365.3 (M+H)⁺, RT=2.60 min

Step 2:N-[(2-{[(cyclobutylmethyl)amino]methyl}-3-fluoro-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

The title compound (40 mg, 43.5%) was prepared in the same manner asExample 2 Step 5.Method C: LC-MS (electrospray): m/z=434.4 (M+H)⁺, RT=3.29 min

Example 46:N-[(2-{[(cyclobutylmethyl)amino]methyl}-1-methyl-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

Step 1: 2-(diethoxymethyl)-1-methyl-1H-indole-6-carbonitrile

To a slurry of sodium hydride (60%, 266 mg, 6.65 mmol) in DMF (1 mL) at0° C. was added a solution of2-(diethoxymethyl)-1H-indole-6-carbonitrile (650 mg, 2.66 mmol) in DMF(1 mL). The reaction was warmed to room temperature for 10 minutesbefore cooling back to 0° C. Methyl iodide (0.33 mL, 5.32 mmol) wasadded dropwise to the slurry and the reaction stirred at 0° C. for 5minutes before warming to room temperature. The reaction was stirred for1 h. The mixture was cooled to 0° C. and quenched via dropwise additionof water (3 mL). The mixture was diluted with EtOAc (5 mL) and thelayers separated. The aqueous layer was extracted twice more with EtOAc(2×5 mL). The organic layers were combined and washed with brine (5 mL),dried over MgSO₄, filtered and concentrated in vacuo to give the crudeproduct as a yellow oil. The crude material was purified bychromatography on SiO₂ [0-50% EtOAc/heptane] to afford the titlecompound (624 mg, 90%) as a white solid.Method B: LC-MS (electrospray): m/z=259.1 (M+H)⁺, RT=0.68 min

Step 2: 1-[2-(diethoxymethyl)-1-methyl-1H-indol-6-yl]methanamine

The title compound (570 mg, 90%) was prepared in the same manner asExample 2 Step 3.Method B: LC-MS (electrospray): m/z=263.3 (M+H)⁺, RT=1.75 min

Step 3:N-[(2-formyl-1-methyl-indol-6-yl)methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide

T3P (50%, 1.6 mL, 2.61 mmol) was added to a mixture of4-oxopyrido[1,2-a]pyrimidine-2-carboxylic acid (454 mg, 2.39 mmol)(Intermediate 1), [2-(diethoxymethyl)-1-methyl-indol-6-yl]methanamine(570 mg, 2.17 mmol) and DIPEA (1.9 mL, 10.9 mmol) in DMF (10 mL), andthe mixture was stirred at ambient temperature overnight. The mixturewas retreated with T3P (50%, 1.6 mL, 2.61 mmol) and DIPEA (1.9 mL, 10.9mmol) and stirred at ambient temperature for 2 h The mixture wasextracted with DCM and H₂O, the layers were separated, the mixture wasextracted with DCM (3×10 mL), the organic layer was passed through aTELOS phase separator and concentrated. The crude material was purifiedby chromatography on SiO₂ [0-100% EtOAc/heptane] to afford the titlecompound (369 mg, 46%) as an off-white solid.Method A: LC-MS (electrospray): m/z=361.1 (M+H)⁺, RT=1.06 min

Step 4:N-[(2-{[(cyclobutylmethyl)amino]methyl}-1-methyl-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

1-cyclobutylmethanamine (87 mg, 1.02 mmol) was added to a solution ofN-[(2-formyl-1-methyl-indol-6-yl)methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide(184 mg, 0.511 mmol) in 1,1,1,3,3,3-Hexafluoro-2-propanol (18.437 mL),and the mixture was stirred at ambient temperature for 30 minutes.1-cyclobutylmethanamine (87 mg, 1.02 mmol) was added, and the mixturewas stirred at ambient temperature for 1 h, then the mixture was heated40° C. for 2 h. A further 1-cyclobutylmethanamine (87 mg, 1.02 mmol) wasadded, and the mixture was stirred at ambient temperature overnight.NaBH₄ (58 mg, 1.53 mmol) was added to the mixture, followed by a fewdrops of MeOH and stirred at ambient temperature for 30 minutes. Themixture was quenched with MeOH (10 mL) at 0° C. and concentrated invacuo. The residue was partitioned between sat. NaHCO₃ (aq) (10 mL) andDCM (10 mL) and the phases separated. The aqueous phase was extractedwith DCM (2×10 mL) and the combined organic phases were passed through aTELOS phase separator and concentrated in vacuo. The residue waspurified by preparative HPLC (Method B) to afford the title compound(119 mg, 54.3%) as a pale yellow solid.Method C: LC-MS (electrospray): m/z=430.6 (M+H)⁺, RT=3.42 min

Example 47:N-[[2-[(Cyclobutylmethylamino)-dideuterio-methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide

Step 1: 6-cyano-1H-indole-2-carboxylic acid

To a suspension of methyl 6-cyano-1H-indole-2-carboxylate (1.00 g, 5.00mmol) in MeOH (15 mL) was added 1 M sodium hydroxide (7.5 mL, 7.49 mmol)at ambient temperature. The mixture was stirred at 40° C. for 2 h. Aftercooling to room temperature, the reaction was acidified with 2M HCl (5mL) and water (20 mL) was added. The resulting precipitate was collectedby vacuum filtration, washed with water (50 mL) and dried in the vacuumoven at 45° C. overnight to afford the title compound (926 mg, 95%) aspale yellow solid.Method A: LC-MS (electrospray): m/z=185.2 (M−H)⁻, RT=0.98 min

Step 2: 6-Cyano-N-(cyclobutylmethyl)-1H-indole-2-carboxamide

To a solution of 6-cyano-1H-indole-2-carboxylic acid (97%, 626 mg, 3.26mmol) in DMF (5 mL) was added di(imidazol-1-yl)methanone (529 mg, 3.26mmol) at ambient temperature. The mixture was stirred at 70° C.(significant production of gas) for 1 h. The mixture was cooled to roomtemperature and 1-cyclobutylmethanamine (361 mg, 4.24 mmol) was added.The mixture was stirred at ambient temperature for 3 h. The mixture wasdiluted with EtOAc (10 mL) and the solid was filtered. To the filtratewere added water (50 mL) and diethyl ether (50 mL) with stirring. Theresulting precipitate was collected by vacuum filtration, washed withwater (20 mL) and diethyl ether (20 mL), and dried in the vacuum oven at45° C. overnight to afford the title compound (550 mg, 63%) as anoff-white solid.Method A: LC-MS (electrospray): m/z=253.9 (M+H)⁺, RT=1.14 min

Step 3: 6-(aminomethyl)-N-(cyclobutylmethyl)-1H-indole-2-carboxamide

The title compound (487 mg, 94%) was prepared in the same manner asExample 2 Step 3.Method C: LC-MS (electrospray): m/z=258.1 (M+H)⁺, RT=2.56 min

Step 4:1-[6-(Aminomethyl)-1H-indol-2-yl]-N-(cyclobutylmethyl)-1,1-dideuterio-methanamine

To a cooled (ice-bath) suspension of lithiumtetrahydro(²H₄)aluminate(1-) (221 mg, 5.83 mmol) in1,4-Dioxane-Anhydrous (5 mL) was added6-(aminomethyl)-N-(cyclobutylmethyl)-1H-indole-2-carboxamide (150 mg,0.583 mmol) in one portion. The ice-bath was removed, and the mixturewas stirred at reflux for 3 h (heating-block temperature 110° C.). Themixture was cooled to 0° C. (ice-bath) and quenched by drop-wiseaddition of a mixture of THF (10 mL) and water (1 mL), followed by 2MNaOH (0.2 mL). The mixture was stirred for 30 minutes at ambienttemperature. The solids were removed by filtration (Kieselguhr) andwashed with THE (20 mL). The filtrate was dried (Na₂SO₄), filtered andconcentrated at reduced pressure to dryness. The residue was dissolvedin chloroform (2 mL) and heptane (10 mL) was added. The resultingprecipitate was collected by vacuum filtration, washed with heptane (5mL) and dried in the vacuum oven at 45° C. for 2 h to afford the titlecompound (114 mg, 69%) as a pale yellow solid.Method C: LC-MS (electrospray): m/z=246.2 (M+H)⁺, RT=2.96 min

Step 5:N-[[2-[(Cyclobutylmethylamino)-dideuterio-methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide

To a solution of 4-oxopyrido[1,2-a]pyrimidine-2-carboxylic acid (78 mg,0.408 mmol) (Intermediate 1),1-[6-(aminomethyl)-1H-indol-2-yl]-N-(cyclobutylmethyl)-1,1-dideuterio-methanamine(86%, 116 mg, 0.408 mmol) and DIPEA (0.21 mL, 1.22 mmol) in DMF (3 mL)was added HATU (170 mg, 0.448 mmol). The reaction was stirred at ambienttemperature overnight. The mixture was partitioned between EtOAc (600mL) and sat. NaHCO₃ solution (20 mL). The organic layer was separated,washed with brine (10 mL), dried (Na₂SO₄), filtered and concentrated atreduced pressure. The residue was purified by open access prep HPLCmethod A. The product containing fractions were combined andconcentrated in vacuo until the bulk of the acetonitrile was removed(water bath temperature 45° C., pressure 100 mbar). The clear solutionwas basified with sat. aq. sodium carbonate solution and extracted with3:1 chloroform/2-propanol (3×40 mL). The combined extracts were washedwith brine (40 mL), dried (Na₂SO₄), filtered and concentrated to drynessat reduced pressure. The residue was triturated with acetonitrile. Thesolid was collected by vacuum filtration, washed with acetonitrile (10mL) and dried in the vacuum oven at 45° C. overnight to afford the titlecompound (63 mg 36%) as a white solid.Method C: LC-MS (electrospray): m/z=418.5 (M+H)⁺, RT=3.14 min

Example 48:N-[[2-[(cyclobutylmethylamino)methyl]-1H-indol-6-yl]methyl]-1H-indazole-4-carboxamide

A pressure vial was charged withN-[(2-formyl-1H-indol-6-yl)methyl]-1-tetrahydropyran-2-yl-indazole-4-carboxamide(150 mg, 0.373 mmol), DCE (4.3 mL) and 1-cyclobutylmethanamine (0.091mL, 0.745 mmol) at ambient temperature. The vial was sealed, and themixture was stirred at 65° C. for 2 h. After cooling to roomtemperature, sodium triacetoxyboranuide (184 mg, 0.866 mmol) was addedand the mixture was heated to 65° C. for 2 h. The mixture waspartitioned between EtOAc (40 mL) and saturated sodium bicarbonatesolution (30 mL). The organic layer was separated, washed with brine (20mL), dried (Na₂SO₄), filtered and concentrated at reduced pressure. Theorange residue was purified via basic reversed phase chromatography(SNAP Ultra 30 g cartridge, MeCN+0.1% NH₃/H₂O+0.1% NH₃ 10 to 90%). Thefractions containing pure product were concentrated in vacuo to give abeige residue. The crude material was redissolved in MeOH (1 mL) and DCM(4 mL) and 4M HCl in dioxane (1 mL) was added. The reaction was stirredat ambient temperature for 5 h. The solvent was removed in vacuo and thecrude pink solid purified using a 2 g-SCX cartridge eluting first withMeOH (10 mL) and then a 2M ammonia in MeOH solution (10 mL). The secondfiltrate was concentrated in vacuo to give the desired product as a anoff-white solid. The compound was freeze dried overnight to afford thetitle compound (78 mg, 53%) as an off-white powder.Method C: LC-MS (electrospray): m/z=388.3 (M+H)⁺, RT=2.96 min

Intermediate 2: tert-Butyl N-(cyclobutylmethyl)-N-prop-2-ynyl-carbamate

To a solution of tert-butyl prop-2-yn-1-ylcarbamate (3.00 g, 19.3 mmol)in DMF-Anhydrous (30 mL) was added sodium hydride (60%, 852 mg, 21.3mmol) at 0° C. The mixture was left to stir for 10 min before additionof (bromomethyl)cyclobutane (2.4 mL, 21.3 mmol). The resulting mixturewas then stirred at ambient temperature overnight. The mixture wasdiluted with water (50 mL) and extracted with diethyl ether (3×50 mL).The combined organic extracts were washed with water (80 mL) and brine(30 mL), dried over MgSO₄, filtered and concentrated under reducedpressure. The crude material was purified by chromatography on SiO₂[Sfar silica D Cartridge 50 g; 0-20% EtOAc in heptane, 12 CVs]. Theproduct containing fractions were combined and concentrated in vacuo toafford the title compound (3.12 g, 13.3 mmol, 69%) as a colourless oil.

Intermediate 3: tert-butyl6-(azidomethyl)-2-[[tert-butoxycarbonyl(cyclobutylmethyl)amino]methyl]pyrrolo[3,2-b]pyridine-1-carboxylate

Step 1: methyl 5-amino-6-bromo-pyridine-3-carboxylate

NBS (6434 mg, 36.1 mmol) was added to a solution of methyl5-aminopyridine-3-carboxylate (5000 mg, 32.9 mmol) in DMF-Anhydrous (50mL) and the mixture was stirred at room temperature over a weekend. Themixture was diluted with water (250 mL) and extracted with EtOAc (250mL). The combined organics were washed with water (250 mL) and brine(250 mL), dried over magnesium sulfate and evaporated to dryness. Thecrude material was purified by chromatography on SiO₂ (Biotage; 100 gSfar Duo; 0-100% EtOAc in heptane) to afford the title compound (2850mg, 25%) as a yellow solid.Method A: LC-MS (electrospray): m/z=231/233 (M+H)⁺, RT=0.95 min

Step 2: methyl6-bromo-5-[(2,2,2-trifluoroacetyl)amino]pyridine-3-carboxylate

TFAA (4.5 mL, 32.2 mmol) was added to a solution of methyl5-amino-6-bromo-pyridine-3-carboxylate (70%, 3540 mg, 10.7 mmol) in DCM(30 mL) and the RM was stirred at ambient temperature for 3 h. The RMwas evaporated to dryness to afford methyl (5250 mg, 99%) as an orangeoil.Method A: LC-MS (electrospray): m/z=327/329 (M+H)⁺, RT=1.10 min

Step 3: methyl2-[[tert-butoxycarbonyl(cyclobutylmethyl)amino]methyl]-1H-pyrrolo[3,2-b]pyridine-6-carboxylate

A solution of methyl6-bromo-5-[(2,2,2-trifluoroacetyl)amino]pyridine-3-carboxylate (66%,5250 mg, 10.6 mmol) in 1,4-Dioxane-Anhydrous (11 mL) was added to asuspension of tert-butyl N-(cyclobutylmethyl)-N-prop-2-ynyl-carbamate(95%, 2490 mg, 10.6 mmol) (Intermediate 2), CuI (304 mg, 1.59 mmol),potassium phosphate (4562 mg, 21.2 mmol) and triphenylphosphane (834 mg,3.18 mmol) in 1,4-Dioxane-Anhydrous (55 mL). The resulting suspensionwas degassed with nitrogen for 10 min, then stirred at 110° C. for 2 h.The mixture was cooled and concentrated under reduced pressure. Theresidue was partitioned between water (30 mL) and EtOAc (30 mL). Theorganic phase was collected, and the aqueous phase was extracted withEtOAc (2×30 mL). The combined organic phases were dried over magnesiumsulfate and concentrated to afford crude material as a brown oil. Thecrude material was purified by chromatography on SiO₂ (Biotage IsoleraFour; 100 g Sfar Duo; 10-60% EtOAc in heptane), then repurified bychromatography on SiO₂ (Biotage Isolera Four; 55 g Sfar Amino D; 10-50%EtOAc in heptane) to afford the title compound (1180 mg, 30%) as a whitesolid.Method A: LC-MS (electrospray): m/z=374.2 (M+H)⁺, RT=1.07 min

Step 4: 1-tert-butyl 6-methyl2-[[tert-butoxycarbonyl(cyclobutylmethyl)amino]methyl]pyrrolo[3,2-b]pyridine-1,6-dicarboxylate

Boc anhydride (947 mg, 4.34 mmol) was added to an ice-cooled solution ofmethyl2-[[tert-butoxycarbonyl(cyclobutylmethyl)amino]methyl]-1H-pyrrolo[3,2-b]pyridine-6-carboxylate(1350 mg, 3.61 mmol) in DCM (28.602 mL), followed by DMAP (44 mg, 0.361mmol). The mixture was warmed to room temperature and stirred for 30minutes. Water (50 mL) was added and the mixture was extracted with DCM(3×50 mL). The combined organics were dried over magnesium sulfate,evaporated to dryness and purified by chromatography on SiO₂ (55 g SfarAmino D; 0-50% EtOAc in heptane) to afford the title compound (1630 mg,95%) as a colourless oil.Method B: LC-MS (electrospray): m/z=474.3 (M+H)⁺, RT=2.28 min

Step 5: tert-butyl2-[[tert-butoxycarbonyl(cyclobutylmethyl)amino]methyl]-6-(hydroxymethyl)pyrrolo[3,2-b]pyridine-1-carboxylate

1M DIBAL in DCM (14 mL, 13.5 mmol) was added to a solution of1-tert-butyl 6-methyl2-[[tert-butoxycarbonyl(cyclobutylmethyl)amino]methyl]pyrrolo[3,2-b]pyridine-1,6-dicarboxylate(1600 mg, 3.38 mmol) in DCM-Anhydrous (32 mL) at −78° C. The mixture wasstirred at this temperature for 2 h. At −78° C. the reaction wasquenched with water (10 mL). The mixture was stirred for 10 min, thenwarmed to room temperature. Water (50 mL) was added and the mixture wasextracted with DCM (3×50 mL). The combined organic phases were driedover magnesium sulfate, evaporated to dryness and purified bychromatography on SiO₂ (Biotage Isolera Four; 55 g Sfar Amino D; 0-100%EtOAc in heptane) to afford the title compound (1160 mg, 74%) as acolourless oil.Method A: LC-MS (electrospray): m/z=446.3 (M+H)⁺, RT=1.25 min

Step 6: tert-butyl6-(azidomethyl)-2-[[tert-butoxycarbonyl(cyclobutylmethyl)amino]methyl]pyrrolo[3,2-b]pyridine-1-carboxylate

DPPA (241 μL, 1.12 mmol) was added to an ice-cooled solution oftert-butyl2-[[tert-butoxycarbonyl(cyclobutylmethyl)amino]methyl]-6-(hydroxymethyl)pyrrolo[3,2-b]pyridine-1-carboxylate(250 mg, 0.561 mmol) and DBU (167 μL, 1.12 mmol) in DMF-Anhydrous (3.125mL). The mixture was stirred at ambient temperature for 24 h A furtheramount of DPPA (241 μL, 1.12 mmol) was added and the mixture was stirredat ambient temperature for 18 h, then heated to 40° C. for 2 h. Themixture was diluted with water (25 mL) and extracted with EtOAc (3×20mL). The combined organics were washed with brine (25 mL), dried overmagnesium sulfate and evaporated to dryness. The crude material waspurified by chromatography on SiO₂ (Biotage Isolera Four; 28 g SfarAmino D; 0-100% EtOAc in heptane) to afford the title compound (140 mg,0.24, 44%) as a colourless oil.Method A: LC-MS (electrospray): m/z=471.3 (M+H)⁺, RT=1.53 min

Example 49:N-[[2-[(cyclobutylmethylamino)methyl]-1H-pyrrolo[3,2-b]pyridin-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide

Step 1: tert-butyl6-(aminomethyl)-2-[[tert-butoxycarbonyl(cyclobutylmethyl)amino]methyl]pyrrolo[3,2-b]pyridine-1-carboxylate

Triphenylphosphane (524 mg, 2.00 mmol) was added to an ice-cooledsolution of tert-butyl6-(azidomethyl)-2-[[tert-butoxycarbonyl(cyclobutylmethyl)amino]methyl]pyrrolo[3,2-b]pyridine-1-carboxylate(94%, 500 mg, 0.999 mmol) (Intermediate 3) in THF (5 mL) and water (0.5mL). The mixture was warmed to room temperature and stirred overnight.The mixture was evaporated to dryness and purified by basic reversephase chromatography to afford (55 mg, 12%) as a colourless oil.Method B: LC-MS (electrospray): m/z=445.3 (M+H)⁺, RT=1.89 min

Step 2: tert-butyl2-[[tert-butoxycarbonyl(cyclobutylmethyl)amino]methyl]-6-[[(4-oxopyrido[1,2-a]pyrimidine-2-carbonyl)amino]methyl]pyrrolo[3,2-b]pyridine-1-carboxylate

A mixture of tert-butyl6-(aminomethyl)-2-[[tert-butoxycarbonyl(cyclobutylmethyl)amino]methyl]pyrrolo[3,2-b]pyridine-1-carboxylate(55 mg, 0.124 mmol), 4-oxopyrido[1,2-a]pyrimidine-2-carboxylic acid (24mg, 0.124 mmol) (Intermediate 1), DIPEA (65 μL, 0.371 mmol) and HATU (52mg, 0.136 mmol) in DMF (1 mL) was stirred at ambient temperature over aweekend. The mixture was partitioned between sat. aq. NaHCO₃ (15 mL) andEtOAc (15 mL). The organic phase was collected, dried over magnesiumsulfate and evaporated to dryness. The crude material was purified bychromatography on SiO₂ (11 g Sfar Amino D; 0-100% EtOAc in heptane) toafford the title compound (51 mg, 57%) as a yellow oil.Method B: LC-MS (electrospray): m/z=617.4 (M+H)⁺, RT=1.91 min

Step 3:N-[[2-[(cyclobutylmethylamino)methyl]-1H-pyrrolo[3,2-b]pyridin-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide

4 M HCl in dioxane (0.17 mL, 0.697 mmol) was added to a solution oftert-butyl2-[[tert-butoxycarbonyl(cyclobutylmethyl)amino]methyl]-6-[[(4-oxopyrido[1,2-a]pyrimidine-2-carbonyl)amino]methyl]pyrrolo[3,2-b]pyridine-1-carboxylate(86%, 50 mg, 0.0697 mmol) in DCM (0.5 mL) and MeOH (0.5 mL). The mixturewas stirred at 40° C. for 2 h, then room temperature overnight. Themixture was evaporated to dryness and purified by preparative HPLC(Method B) to afford the title compound (15 mg, 50%) as a white powder.Method C: LC-MS (electrospray): m/z=417.3 (M+H)⁺, RT=2.32 min

Intermediate 12: tert-butylN-[[6-(aminomethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]methyl]-N-(cyclobutylmethyl)carbamate

Step 1: tert-butylN-[3-(2-amino-6-chloro-3-pyridyl)prop-2-ynyl]-N-(cyclobutylmethyl)carbamate

To a solution of 6-chloro-3-iodopyridin-2-amine (0.96 g, 3.77 mmol) inTHF-Anhydrous (5 mL) and triethylamine (9.0 mL, 64.6 mmol) was addedpalladium(2+) chloride-triphenylphosphane (1:2:2) (26 mg, 0.0377 mmol)and triphenylphosphane (20 mg, 0.0755 mmol) at ambient temperature. Thesolution was de-gassed by bubbling nitrogen into the solution for 15minutes. Then copper (1+) iodide (14 mg, 0.0755 mmol) and tert-butylN-(cyclobutylmethyl)-N-prop-2-ynyl-carbamate (1.01 g, 4.53 mmol)(Intermediate 2) were added sequentially and the reaction was stirredunder nitrogen atmosphere for 4 h. The precipitate (triethylaminehydroiodide) was collected by filtration and washed with EtOAc (˜20 mL).The filtrate was concentrated at reduced pressure and the residue waspurified by chromatography on SiO₂ [BIOTAGE Sfar Silica D-Duo 60 μmcartridge, 0-50% EtOAc in heptane 12CVs]. The product containingfractions were combined and concentrated in vacuo to afford the titlecompound (1.31 g, 92%) as orange oil, that solidified upon standing togive a brown solid.Method C: LC-MS (electrospray): m/z=350.3 (M+H)⁺, RT=4.54 min

Step 2: tert-butylN-[(6-chloro-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl]-N-(cyclobutylmethyl)carbamate

To a stirred solution of tert-butylN-[3-(2-amino-6-chloro-3-pyridyl)prop-2-ynyl]-N-(cyclobutylmethyl)carbamate(93%, 1.41 g, 3.74 mmol) in NMP-Anhydrous (15 mL) was added potassium2-methylpropan-2-olate (0.84 g, 7.49 mmol) at 0° C. (the colour of thesolution turned from orange to black within seconds). After warming toroom temperature, the solution was stirred at ambient temperature for 16h under nitrogen atmosphere. Saturated aqueous ammonium chloridesolution (5 mL) was added and the resulting mixture was partitionedbetween EtOAc (100 mL) and water (80 mL). The organic layer wasseparated, and the aqueous layer was extracted with EtOAc (50 mL). Thecombined organic layers were washed with water (2×50 mL) and brine (30mL), dried (Na₂SO₄), filtered and concentrated at reduced pressure. Theresidue was purified by chromatography on SiO₂ [BIOTAGE Sfar SilicaD-Duo 60 μm cartridge 50 g, 0-50% EtOAc in heptane 12CVs]. The productcontaining fractions were combined and concentrated in vacuo. Theresidue (orange solid) was triturated with heptane. The resulting solidwas collected by vacuum filtration, washed with heptane (10 mL) anddried in the vacuum oven at 45° C. for 2 h to afford the title compound(650 mg, 47%) as white solid.Method C: LC-MS (electrospray): m/z=350.3/352.3 (M+H)⁺, RT=4.60 min

Step 3: tert-butylN-[(6-cyano-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl]-N-(cyclobutylmethyl)carbamate

To a de-gassed suspension of tert-butylN-[(6-chloro-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl]-N-(cyclobutylmethyl)carbamate(585 mg, 1.67 mmol) and zinc dicyanide (216 mg, 1.84 mmol) inNMP-Anhydrous (7 mL) in a pressure vial was added tBuXPhos Pd G3 (33 mg,0.0418 mmol) at ambient temperature. The vial was sealed, and thereaction was stirred at 120° C. for 2 h. After cooling to roomtemperature, the mixture was diluted with water (30 mL) and extractedwith ethyl acetate (2×50 mL). The combined organic extracts were washedwith water (50 mL), saturated NaHCO₃ (aq) solution (20 mL) and brine (20mL), dried over (Na₂SO₄), filtered and concentrated at reduced pressure.The residue was purified by chromatography on SiO₂ [BIOTAGE Sfar SilicaD-Duo 60 μm cartridge 25 g, 0-100% EtOAc in heptane 12CVs]. The productcontaining fraction (fraction 3) was concentrated in vacuo to afford thetitle compound (475 mg, 79%) as white solid.Method C: LC-MS (electrospray): m/z=341.4 (M+H)⁺, RT=4.22 min

Step 4: tert-butylN-[[6-(aminomethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]methyl]-N-(cyclobutylmethyl)carbamate

To a de-gassed suspension of tert-butylN-[(6-cyano-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl]-N-(cyclobutylmethyl)carbamate(475 mg, 1.40 mmol) in Ethanol (20 mL) were added 7 M ammonia in MeOH(5.0 mL, 35.0 mmol) and Raney-nickel (164 mg, 2.79 mmol) at ambienttemperature. The mixture was degassed again and stirred under anatmosphere of hydrogen for 16 h. The catalyst was removed by filtration(Celite) and washed with ethanol (approximately 20 mL). The filtrate wasconcentrated at reduced pressure to dryness to afford the title compound(480 mg, 95) as a greenish oil.Method C: LC-MS (electrospray): m/z=345.4 (M+H)⁺, RT=3.58 min

Example 71:N-[[2-[(cyclobutylmethylamino)methyl]-1H-pyrrolo[2,3-b]pyridin-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide

Step 1:N-[[2-[(cyclobutylmethylamino)methyl]-1H-pyrrolo[2,3-b]pyridin-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide

The tile compound (345 mg, 64%) was prepared in the same manner asprecursor in Example 42, using Intermediate 12.Method C: LC-MS (electrospray): m/z=517.4 (M+H)⁺, RT=3.92 min

Step 2:N-[[2-[(cyclobutylmethylamino)methyl]-1H-pyrrolo[2,3-b]pyridin-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide

To a solution of tert-butylN-(cyclobutylmethyl)-N-[[6-[[(4-oxopyrido[1,2-a]pyrimidine-2-carbonyl)amino]methyl]-1H-pyrrolo[2,3-b]pyridin-2-yl]methyl]carbamate(90%, 730 mg, 1.27 mmol) in DCM (5 mL) was added TFA (5 mL) at ambienttemperature. The mixture was stirred at ambient temperature until theproduction of gas ceased (˜1 h). The mixture was concentrated to drynessat reduced pressure. The residue was dissolved in MeOH (6 mL) andpurified by open access prep HPLC Method B. The product containingfractions were combined and concentrated in vacuo to dryness. Theresidue (colourless oil) was triturated with acetonitrile (5 mL). Theresulting solid was collected by vacuum filtration, washed withacetonitrile (2 mL) and heptane (5 mL) and dried in the vacuum oven at45° C. overnight to the title compound (345 mg, 64%) as a white solid.Method C: LC-MS (electrospray): m/z=417.4 (M+H)⁺, RT=2.85 min

Example 72:N-[(2-{[(cyclobutylmethyl)amino]methyl}-1H-1,3-benzodiazol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

Step 1: tert-Butyl N-[(5-cyano-1H-benzimidazol-2-yl)methyl]carbamate

To a suspension of 3,4-diaminobenzonitrile (98%, 0.50 g, 3.68 mmol) andN-(tert-butoxycarbonyl)glycine (0.71 g, 4.05 mmol) in DCE (10 mL) wasadded added N-ethyl-N-isopropyl-propan-2-amine (3.2 mL, 18.4 mmol) andT3P (50%, 4.4 mL, 7.36 mmol) in EtOAc at ambient temperature. Themixture was stirred in a pressure vial for 24 h at 100° C. After coolingto room temperature, the mixture was poured into saturated aqueousNaHCO₃ solution (25 mL). The organic layer was separated and the aqueouswas extracted with DCE (2×20 mL). The combined organic layers werewashed with brine (20 mL), dried (Na₂SO₄), filtered and concentrated atreduced pressure. The residue was purified by chromatography on SiO₂[SNAP Cartridge KP-Sil 25 g; 0-100% EtOAc in heptane, 12 CVs]. Theproduct containing fractions were combined and concentrated in vacuo toafford an orange oil. The product was re-purified by chromatography onSiO₂ [SNAP Cartridge KP-Sil 25 g; 0-100% EtOAc in DCM, 12 CVs]. Theproduct containing fractions were combined and concentrated in vacuo.The residue was triturated with EtOAc/heptane to afford the titlecompound (260 mg, 25%) as a grey solid.Method C: LC-MS (electrospray): m/z=273.1 (M−H)⁻, RT=2.33 min

Step 2: tert-ButylN-[[6-(aminomethyl)-1H-benzimidazol-2-yl]methyl]carbamate

The title compound (255 mg, 95.5%) was prepared in the same manner asExample 2 Step 3.Method C: LC-MS (electrospray): m/z=277.2 (M+H)⁺, RT=1.85 min

Step 3: tert-ButylN-[[6-[[(4-oxopyrido[1,2-a]pyrimidine-2-carbonyl)amino]methyl]-1H-benzimidazol-2-yl]methyl]carbamate

To a solution of 4-oxopyrido[1,2-a]pyrimidine-2-carboxylic acid (180 mg,0.945 mmol) (Intermediate 1), tert-butylN-[[6-(aminomethyl)-1H-benzimidazol-2-yl]methyl]carbamate (95%, 250 mg,0.859 mmol) and DIPEA (0.45 mL, 2.58 mmol)) in DMF (7.5 mL) was addedHATU (392 mg, 1.03 mmol). The reaction was stirred at ambienttemperature overnight. The mixture was partitioned between EtOAc (80 mL)and sat. NaHCO₃ solution (500 mL). The organic layer was separated,washed with water (50 mL) and brine (20 mL), dried (Na₂SO₄), filteredand concentrated at reduced pressure. The residue was purified bypreparative HPLC (Method B) to afford the title compound (220 mg, 55.9%)as a colourless solid.Method C: LC-MS (electrospray): m/z=449.3 (M+H)⁺, RT=2.30 min

Step 4:N-[[2-(Aminomethyl)-3H-benzimidazol-5-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamidehydrochloride

To a solution of tert-butylN-[[6-[[(4-oxopyrido[1,2-a]pyrimidine-2-carbonyl)amino]methyl]-1H-benzimidazol-2-yl]methyl]carbamate(202 mg, 0.450 mmol) in THF (3 mL) was added 4 M hydrogen chloride in1,4-dioxane (4.0 mL, 16.0 mmol) and the mixture was stirred at ambienttemperature for 2 h. The volatiles were removed at reduced pressure. Theresidue was dissolved in MeOH (3 mL) and diethyl ether (20 mL) wasadded. The resulting precipitate was collected by vacuum filtration,washed with diethyl ether (10 mL) and dried in the vacuum oven at 45° C.for 2 h to afford the title compound (165 mg, 92%) as a white solid.Method C: LC-MS (electrospray): m/z=449.3 (M+H)⁺, RT=2.30 min

Step 5:N-[(2-{[(cyclobutylmethyl)amino]methyl}-1H-1,3-benzodiazol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

A solution ofN-[[2-(aminomethyl)-3H-benzimidazol-5-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamidehydrochloride (100 mg, 0.260 mmol), N-ethyl-N-isopropyl-propan-2-amine(0.14 mL, 0.780 mmol) and cyclobutanecarbaldehyde (95%, 23 mg, 0.260mmol) in Ethanol (5 mL) was stirred at ambient temperature for 1 h. Themixture was then cooled to 0° C. (ice bath) and sodium boranuide (10 mg,0.260 mmol) was added. The reaction was allowed to warm to roomtemperature and was stirred for 1 h. The reaction was partitionedbetween ethyl acetate (40 mL) and 2M aq. Na₂CO₃ solution (30 mL). Theorganic layer was separated, washed with brine (20 mL), dried (Na₂SO₄),filtered and concentrated at reduced pressure. The residue was purifiedby open access prep HPLC Method B. The product containing fractions werecombined and concentrated to dryness. The residue was dissolved in a 1:1(v/v) mixture of acetonitrile and water (4 mL). The resulting solutionwas lyophilised to afford the title compound (36 mg, 33%) as a whitesolid.Method C: LC-MS (electrospray): m/z=417.3 (M+H)⁺, RT=2.28 min

Example 50:N-(1H-indol-6-ylmethyl)-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide

HATU (219 mg, 0.575 mmol) was added to the mixture of4-oxopyrido[1,2-a]pyrimidine-2-carboxylic acid (109 mg, 0.575 mmol)(Intermediate 1) and DIPEA (0.24 mL, 1.37 mmol) in DMF (5.6 mL) and themixture was stirred at DMF (5.6 mL). 1H-indol-6-ylmethanamine (70 mg,0.479 mmol) was added after 10 min. and the reaction stirred at ambienttemperature overnight. Water (15 mL) was added to the reaction and themixture was extracted with DCM (15 mL). The organic phase was washedwith brine (4×15 mL), dried, filtered and reduced in vacuo. The crudewas purified by preparative HPLC (Method B) to afford the title compound(30 mg, 19%) as an off-white solid.Method C: LC-MS (electrospray): m/z=319.2 (M+H)⁺, RT=2.55 min

Example 51:N-(1H-indol-2-ylmethyl)-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide

The title compound was prepared in the same manner as Example 49, usingDIPEA (0.36 mL, 2.05 mmol) as the amine was a salt.Method C: LC-MS (electrospray): m/z=319.2 (M+H)⁺, RT=2.75 min

Example 52:N-(indolizin-2-ylmethyl)-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide

The title compound was prepared in the same manner as Example 49Method C: LC-MS (electrospray): m/z=319.2 (M+H)⁺, RT=2.74 min

Intermediate 4: 7-ethynyl-1-tetrahydropyran-2-yl-indazole

Step 1: 7-bromo-1-tetrahydropyran-2-yl-indazole

7-bromo-1H-indazole (1 g, 5.08 mmol), TsOH, H₂O (193 mg, 1.02 mmol) and3,4-dihydro-2H-pyran (923 μL, 10.2 mmol) were combined in DCM (50 mL)and the mixture stirred at ambient temperature overnight. The mixturewas quenched with saturated NaHCO₃ (aq) (50 mL) and stirred briskly for5 mins. The phases were separated, and the aqueous phase extracted withDCM (2×50 mL). The combined organic layers were dried over Na₂SO₄ andevaporated under vacuum. The residue was purified by chromatography onSiO₂ (50 g Sfar Duo, eluting with EtOAc/heptane 0-100%) to afford thetitle compound (543 mg, 36%).Method B: LC-MS (electrospray): m/z=281.1/283.1 (M+H)⁺, RT=1.77 min

Step 2: trimethyl-[2-(1-tetrahydropyran-2-ylindazol-7-yl)ethynyl]silane

A mixture of 4-bromo-1-tetrahydropyran-2-yl-indazole (2.50 g, 8.89 mmol)and triethylamine (5.9 mL, 42.5 mmol) in DMF-Anhydrous (15 mL) wasdegassed for 5 mins. Ethynyl(trimethyl)silane (3.7 mL, 26.7 mmol), CuI(170 mg, 0.889 mmol) and PdCl₂dppf (652 mg, 0.889 mmol) were added, themixture was degassed for a further 5 mins before the mixture was stirredat 100° C. for 2 h. The mixture was allowed to cool to room temperatureand was concentrated in vacuo to remove the DMF. The material wasdissolved in DCM (10 mL), passed through a plug of Celite, washed withDCM (100 mL) and concentrated to give a crude brown solid. The crudematerial was dry loaded onto silica and purified by chromatography onSiO₂ (50 g, 0-30% EtOAc/heptane) to afford the title compound (2.38 g,88%) as a brown oil.

Method B: LC-MS (electrospray): m/z=299.3 (M+H)⁺, RT=2.15 min

Step 3: 7-ethynyl-1-tetrahydropyran-2-yl-indazole

Dipotassium carbonate (2.20 g, 15.9 mmol) was added to a solution oftrimethyl-[2-(1-tetrahydropyran-2-ylindazol-4-yl)ethynyl]silane (2.38 g,7.96 mmol) in MeOH (15 mL), and the brown mixture was stirred at ambienttemperature for 2 h (K₂CO₃ was not entirely in solution). The solventwas removed in vacuo. The residue was diluted with DCM (20 mL) and H₂O(10 mL). The layers were separated, and the aqueous phase was extractedwith DCM (3×15 mL). The combined organic extracts were washed with brine(20 mL), passed through a TELOS phase separator and concentrated invacuo. The crude material was dry loaded onto a 30 g KP-Sil cartridgeand purified by chromatography on SiO₂ (0-20% EtOAc/heptane) to affordthe title compound (1.69 g, 89%) as a dark red solid.Method J: LC-MS (electrospray): m/z=227.1 (M+H)⁺, RT=0.62 min

Intermediate 5: O1-tert-butyl O2-methyl6-(azidomethyl)indole-1,2-dicarboxylate

Step 1: O1-tert-butyl O2-methyl 6-methylindole-1,2-dicarboxylate

Boc anhydride (13.84 g, 63.4 mmol) was added to a mixture of methyl6-methyl-1H-indole-2-carboxylate (10.00 g, 52.9 mmol) and DMAP (1.00 g,8.19 mmol) in Acetonitrile (100 mL). The mixture was stirred at ambienttemperature for 10 mins before being stirred at 45° C. overnight. Themixture was cooled to room temperature. The solvent was removed in vacuoto give an orange solid. The solid was dissolved in EtOAc (50 mL) andwashed with H₂O (20 mL). The layers were separated, and the aqueouslayer extracted with EtOAc (3×30 mL). The combined organic phases werewashed with brine (50 mL), dried over MgSO₄, filtered and concentratedin vacuo. The crude material was purified by chromatography on SiO₂ (100g KP-Sil, eluting with EtOAc/heptane 0-50%) to afford the title compound(14.21 g, 93%) as a pale orange solid.Method B: LC-MS (electrospray): m/z=290.2 (M+H)⁺, RT=2.01 min

Step 2: O1-tert-butyl O2-methyl 6-(bromomethyl)indole-1,2-dicarboxylate

A 250 mL RBF was charged with O1-tert-butyl O2-methyl6-methylindole-1,2-dicarboxylate (3.00 g, 10.4 mmol) in DCE (150 mL),1-bromopyrrolidine-2,5-dione (1.75 g, 9.85 mmol) and2,2′-(E)-diazene-1,2-diylbis(2-methylpropanenitrile) (170 mg, 1.04 mmol)were added, and the mixture was stirred at 75° C. for 2 h. The mixturewas cooled to room temperature, and the solvent was removed in vacuo.The crude material was purified by chromatography on SiO₂ (100 g KP-Sil,0-10% EtOAc/heptane) to afford the title compound (3.12 g, 79%) as anoff white solid.Method B: LC-MS (electrospray): m/z=368.1/370.2 (M+H)⁺, RT=1.99 min

Step 3: O1-tert-butyl O2-methyl 6-(azidomethyl)indole-1,2-dicarboxylate

O1-tert-butyl O2-methyl 6-(bromomethyl)indole-1,2-dicarboxylate (1.80 g,4.89 mmol) was dissolved in DMF (8.0488 mL) followed by addition of NaI(72 mg, 0.477 mmol) and NaN₃ (794 mg, 12.2 mmol), and the reaction wasstirred at ambient temperature for 2 h. The mixture was quenched withH₂O (10 mL), and extracted with EtOAc (3×20 mL). The combined organiclayers were washed with brine (2×50 mL), dried over MgSO₄, filtered andconcentrated in vacuo. The crude material was purified by chromatographyon SiO₂ (0-40% EtOAc/heptane) to afford the title compound (1.37 g, 78%)as a yellow oil.Method B: LC-MS (electrospray): m/z=331.2 (M+H)⁺, RT=1.97 min

Example 53:N-[(6-{[4-(1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl]methyl}-1H-indol-2-yl)methyl]cyclopropanamine

Step 1: O1-tert-butyl O2-methyl 6-[[4-(1-tetrahydropyran-2-ylindazol-4-yl)triazol-1-yl]methyl]indole-1,2-dicarboxylate

Sodium ascorbate (1.24 g, 6.20 mmol) and CuSO₄ (41 mg, 0.254 mmol) wereadded to a mixture of 1-tert-butyl 2-methyl6-(azidomethyl)indole-1,2-dicarboxylate (1.37 g, 4.14 mmol)(Intermediate 5) and 4-ethynyl-1-tetrahydropyran-2-yl-indazole (1.03 g,4.55 mmol) (Intermediate 4) in DMF (25 mL) and water (10 mL), and themixture was stirred at ambient temperature for 3.5 h A further amount ofCuSO₄ (41 mg, 0.254 mmol) was added, and the mixture was stirred atambient temperature overnight. The mixture was diluted with 3:1chloroform/isopropanol (40 mL) and water (30 mL) and the phasesseparated. The aqueous phase was extracted with 3:1chloroform/isopropanol (2×30 mL) and the combined organic layers washedwith water (40 mL), passed through a TELOS phase separator andevaporated under vacuum. The crude material was purified bychromatography on SiO₂ (0-50% EtOAc/heptane, 50 g D Sfar) to afford thetitle compound (1.80 g, 71%) as an off white solid.Method B: LC-MS (electrospray): m/z=557.3 (M+H)⁺, RT=1.98 min

Step 2: tert-butyl2-(hydroxymethyl)-6-[[4-(1-tetrahydropyran-2-ylindazol-4-yl)triazol-1-yl]methyl]indole-1-carboxylate

1 M DIBAL-H (1M in DCM) (6.5 mL, 6.47 mmol) was slowly added to asolution of O1-tert-butyl O2-methyl6-[[4-(1-tetrahydropyran-2-ylindazol-4-yl)triazol-1-yl]methyl]indole-1,2-dicarboxylate(1.80 g, 3.24 mmol) in DCM-Anhydrous (40 mL) at −78° C., and the mixturewas stirred at −78° C. for 1 h. The mixture was retreated with 1 MDIBAL-H (1M in DCM) (3.2 mL, 3.24 mmol) and was stirred at −78° C. for 1h then stirred at −40° C. for 2 h. A further 1 M DIBAL-H (1.6 mL, 1.62mmol) was added to the mixture and stirred at −40° C. for 1.5 h. Themixture was slowly quenched with MeOH (5 mL) at −40° C., stirred for 5mins, then H₂O (5 mL) was added dropwise, and the mixture was vigorouslystirred at ambient temperature for 10 mins. 1 M NaOH (aq) (5 mL) wasadded to help solubilise the mixture. The organic solvent was removed invacuo. The mixture was diluted with DCM (40 mL) and H₂O (20 mL), thelayers were separated, the mixture was extracted with DCM (3×10 mL), theorganic layers were washed with brine, passed through a TELOS phaseseparator and concentrated. The crude material was purified bychromatography on SiO₂ (0-70% EtOAc/heptane) to afford the titlecompound (1.30 g, 74%) as a white solid.Method B: LC-MS (electrospray): m/z=529.3 (M+H)⁺, RT=1.79 min

Step 3: tert-butyl2-formyl-6-[[4-(1-tetrahydropyran-2-ylindazol-4-yl)triazol-1-yl]methyl]indole-1-carboxylate

A mixture of tert-butyl2-(hydroxymethyl)-6-[[4-(1-tetrahydropyran-2-ylindazol-4-yl)triazol-1-yl]methyl]indole-1-carboxylate(1.45 g, 2.75 mmol) and dioxomanganese (2.39 g, 27.5 mmol) in DCE (80mL) was stirred at reflux (90° C.) for 1 h. The reaction was cooled toroom temperature and filtered through a pad of Celite to remove thesolid. The solid was washed with EtOAc (50 mL). The filtrate wascollected, and the solvent was removed in vacuo to afford the titlecompound (1.37 g, 87%) as a yellow foam.Method B: LC-MS (electrospray): m/z=527.2 (M+H)⁺, RT=1.93 min

Step 4:N-[(6-{[4-(1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl]methyl}-1H-indol-2-yl)methyl]cyclopropanamine

cyclopropanamine (53 μL, 0.760 mmol) was added to a solution oftert-butyl2-formyl-6-[[4-(1-tetrahydropyran-2-ylindazol-4-yl)triazol-1-yl]methyl]indole-1-carboxylate(200 mg, 0.380 mmol) in DCE (0.72 mL) and the mixture was stirred 60° C.for 1 h. The mixture was cooled to room temperature and added drop-wiseover 5 min to a solution of NaBH₄ (14 mg, 0.380 mmol) in Ethanol (1.44mL). The RM was stirred at ambient temperature overnight. A furtheramount of NaBH₄ (14 mg, 0.380 mmol) was added to the mixture, andstirred at ambient temperature for 2 h. The mixture was quenched withwater and extracted with DCM (3×20 mL), the organic phases were passedthrough a TELOS phase separator and concentrated in vacuo. The mixturewas diluted with MeOH (1.4 mL) and then treated with HCl (4M in dioxane,1.4 mL), and the mixture was stirred at ambient temperature for 6 h. Themixture was stirred at room temperature overnight. The mixture wasstirred at 45° C. for 30 mins, before being concentrated in vacuo. Thecrude material was purified by preparative HPLC (Method B) and a bespokemethod to afford the title compound (32 mg, 22%) as a white solid.Method C: LC-MS (electrospray): m/z=384.3 (M+H)⁺, RT=2.84 minThe compounds in Table 2 were prepared in the same manner as Example 52using commercial amines or described intermediates.

TABLE 2 LCMS Compound LCMS Retention No Name Structure method time MassIon  54 (1R,2S)-2- [[6-[[4-(1H- indazol-4- yl)triazol-1- yl]methyl]-1H-indol-2- yl]methylamino] cyclopentanol

C 2.73 428.4  55 N-[[6-[[4- (1H-indazol- 4-yl)triazol- 1-yl]methyl]-1H-indol-2- yl]methyl] cyclopentanamine

C 3.24 412.4  56 N- (cyclopropylmethyl)- 1-[6-[[4-(1H- indazol-4-yl)triazol-1- yl]methyl]- 1H-indol-2- yl]methanamine

C 2.98 398.4  57 1-[[[6-[[4- (1H-indazol- 4-yl)triazol- 1-yl]methyl]-1H-indol-2- yl]methylamino] methyl] cyclobutanol

C 2.67 428.5 122 4-(1-{[2-({2- azaspiro[3.3] heptanean- 2-yl}methyl)-1H-indol-6- yl]methyl}- 1H-1,2,3- triazol-4-yl)- 1H-indazole

C 3.46 424.5

Example 58:N-(cyclobutylmethyl)-1-[6-[[4-(1H-indazol-4-yl)triazol-1-yl]methyl]-1H-indol-2-yl]methanamine

tert-butyl 2-formyl-6-[[4-(1-tetrahydropyran-2-ylindazol-4-yl)triazol-1-yl]methyl]indole-1-carboxylate (50mg, 0.10 mmol) and 1-cyclobutylmethanamine (16 mg, 0.19 mmol) werecombined in 1,1,1,3,3,3-Hexafluoro-2-propanol (2 mL) and the mixtureincubated at ambient temperature for 30 minutes. NaBH₄ (11 mg, 0.28mmol) was added with a few drops MeOH and the mixture incubated brieflyat ambient temperature. The reaction was quenched with MeOH (20 mL) andevaporated under vacuum. The residue was partitioned between saturatedNaHCO₃ (aq) (10 mL) and DCM (10 mL) and the phases separated. Theaqueous phase was extracted with DCM (2×15 mL) and the combined organiclayers dried over Na₂SO₄ and evaporated under vacuum. The residue wasredissolved in MeOH (5 mL) and treated with 4M HCl in Dioxane (5 mL) andincubated at ambient temperature overnight. The mixture was evaporatedunder vacuum and the residue purified by preparative HPLC (Method B) toafford the title compound (13 mg, 33%) as an off-white solid.Method D: LC-MS (electrospray): m/z=412.3 (M+H)⁺, RT=4.12 min

Example 59:N-(cyclobutylmethyl)-1-[6-[[4-(1H-indazol-4-yl)triazol-1-yl]methyl]-1H-pyrrolo[3,2-b]pyridin-2-yl]methanamine

Step 1: tert-butyl2-[[tert-butoxycarbonyl(cyclobutylmethyl)amino]methyl]-6-[[4-(1-tetrahydropyran-2-ylindazol-4-yl)triazol-1-yl]methyl]pyrrolo[3,2-b]pyridine-1-carboxylate

A mixture of 4-ethynyl-1-tetrahydropyran-2-yl-indazole (19 mg, 0.0850mmol) (Intermediate 4), tert-butyl6-(azidomethyl)-2-[[tert-butoxycarbonyl(cyclobutylmethyl)amino]methyl]pyrrolo[3,2-b]pyridine-1-carboxylate(40 mg, 0.0850 mmol) (Intermediate 3), copper sulfate (2.7 mg, 0.0170mmol) and sodium ascorbate (19 mg, 0.0935 mmol) in DMF (1 mL) and water(0.2 mL) was stirred at ambient temperature overnight. The mixture wasdiluted with water and 10% MeOH in DCM. The organic phase was collectedusing a Telos phase separator, evaporated to dryness under reducedpressure and purified by chromatography on SiO₂ (KP—NH; 0-100% EtOAc inheptane, then 0-20% MeOH in EtOAc) to afford the title compound (26 mg,44%) as a colourless oil.Method A: LC-MS (electrospray): m/z=697.5 (M+H)⁺, RT=1.81 min

Step 2:N-(cyclobutylmethyl)-1-[6-[[4-(1H-indazol-4-yl)triazol-1-yl]methyl]-1H-pyrrolo[3,2-b]pyridin-2-yl]methanamine

4 M HCl in dioxane (0.19 mL, 0.746 mmol) was added to a solution oftert-butyl2-[[tert-butoxycarbonyl(cyclobutylmethyl)amino]methyl]-6-[[4-(1-tetrahydropyran-2-ylindazol-4-yl)triazol-1-yl]methyl]pyrrolo[3,2-b]pyridine-1-carboxylate(26 mg, 0.0373 mmol) in MeOH (1 mL) and the mixture was stirred at roomtemperature over a weekend. The mixture was evaporated to dryness,purified by preparative HPLC (Method B) and freeze dried to afford thetitle compound (7.0 mg, 45%) as a white powder.Method D: LC-MS (electrospray): m/z=413.4 (M+H)⁺, RT=2.45 min

Intermediate 6: tert-butylN-[[6-(azidomethyl)-1H-pyrrolo[3,2-c]pyridin-2-yl]methyl]-N-(cyclobutylmethyl)carbamate

Step 1: methyl 4-amino-5-bromo-pyridine-2-carboxylate

NBS (2.29 g, 12.9 mmol) was added to a solution of methyl4-aminopyridine-2-carboxylate (98%, 2.00 g, 12.9 mmol) in DCE (60 mL)and the mixture was stirred at room temperature overnight. The mixturewas diluted with water (50 mL) and extracted with EtOAc (3×50 mL). Thecombined organics were washed with brine (100 mL), dried over magnesiumsulfate and evaporated to dryness to afford the title compound (2.47 g,79%) as an off white solid.Method B: LC-MS (electrospray): m/z=231.1/233.1 (M+H)⁺, RT=1.16 min

Step 2: methyl5-bromo-4-[(2,2,2-trifluoroacetyl)amino]pyridine-2-carboxylate

TFAA (4.5 mL, 32.0 mmol) was added to a solution of methyl4-amino-5-bromo-pyridine-2-carboxylate (2.47 g, 10.7 mmol) in DCM (30mL) and the mixture was stirred at ambient temperature overnight.Initially the white cloudy mixture was fully in solution and colourlessby morning. The mixture was evaporated to dryness to afford product as aTFA salt (4.7 g, 97%). 55 mg of the salt was taken, diluted with DCM (2mL) and sat. aq. NaHCO₃ (2 mL), the layers were separated, the aqueouslayer was extracted with DCM (3×2 mL), the organic layers were passedthrough a TELOS phase separator and concentrated to give 32 mg of thetitle compound (32 mg, 0.85%) as a white solid.Method B: LC-MS (electrospray): m/z=327.0/329.0 (M+H)⁺, RT=0.90 min

Step 3: methyl2-[[tert-butoxycarbonyl(cyclobutylmethyl)amino]methyl]-1H-pyrrolo[3,2-c]pyridine-6-carboxylate

A mixture of methyl5-bromo-4-[(2,2,2-trifluoroacetyl)amino]pyridine-2-carboxylate (1.63 g,4.99 mmol), tert-butyl N-(cyclobutylmethyl)-N-prop-2-ynyl-carbamate(1.34 g, 5.99 mmol) (Intermediate 2) and 1,1,3,3-tetramethylguanidine(1.9 mL, 15.0 mmol) in DMF-Anhydrous (27.668 mL) was degassed for 5mins, iodocopper (96 mg, 0.499 mmol) and dichloropalladiumtriphenylphosphane (422 mg, 0.599 mmol) were added, the mixture wasdegassed for a further 5 mins before being stirred at 65° C. overnight.The mixture was re-treated with dichloropalladium triphenylphosphane(422 mg, 0.599 mmol) and iodocopper (96 mg, 0.499 mmol), the mixture wasdegassed for 10 mins, then the mixture was stirred at 65° C. for afurther 2 h. The mixture was cooled to room temperature, filteredthrough Celite and washed with EtOAc (300 mL). The mixture wasconcentrated and purified by chromatography on SiO₂ (Sfar amino D Duo 55g, 0-100% EtOAc/heptane) gave impure material with a large amount oftriphenylphosphine oxide byproduct. The material was loaded onto a 5 gSCX cartridge, MeOH was passed through, followed by 2.5 M NH₃ in MeOHsolution. The latter fractions were collected and concentrated to affordthe title compound (784 mg, 21%) as a brown oil.

Step 4: tert-butylN-(cyclobutylmethyl)-N-[[6-(hydroxymethyl)-1H-pyrrolo[3,2-c]pyridin-2-yl]methyl]carbamate

1 M DIBAL-H (1M in DCM) (2.2 mL, 2.25 mmol) was slowly added to asolution of methyl2-[[tert-butoxycarbonyl(cyclobutylmethyl)amino]methyl]-1H-pyrrolo[3,2-c]pyridine-6-carboxylate(50%, 839 mg, 1.12 mmol) in DCM-Anhydrous (13.879 mL) at −78° C., andthe mixture was stirred at −78° C. for 2 h. The mixture was warmed to−40° C., re-treated with 1 M DIBAL-H (1M in DCM) (1.1 mL, 1.12 mmol) andstirred at −40° C. for 3.5 h. The mixture was slowly quenched with MeOH(5 mL) at −40° C., stirred for 5 mins, then H₂O (5 mL) was addeddropwise, and the mixture was vigorously stirred at ambient temperaturefor 10 mins. 1 M NaOH (aq) (5 mL) was added to help solubilise themixture. The organic solvent was removed in vacuo. The mixture wasdiluted with DCM (40 mL) and H₂O (20 mL), the layers were separated, themixture was extracted with DCM (3×10 mL), the organic layers were washedwith brine, passed through a TELOS phase separator and concentrated invauo.The crude product was purified by chromatography on SiO₂ (0-70%EtOAc/heptane) to afford the tite compound (128 mg, 31%) as a pale brownsolid.Method B: LC-MS (electrospray): m/z=346.3 (M+H)⁺, RT=1.61 min

Step 5: tert-butylN-[[6-(azidomethyl)-1H-pyrrolo[3,2-c]pyridin-2-yl]methyl]-N-(cyclobutylmethyl)carbamate

diphenyl phosphorazidate (0.16 mL, 0.741 mmol) was added to anice-cooled solution of tert-butylN-(cyclobutylmethyl)-N-[[6-(hydroxymethyl)-1H-pyrrolo[3,2-c]pyridin-2-yl]methyl]carbamate(128 mg, 0.371 mmol) and DBU (0.11 mL, 0.741 mmol) in DMF-Anhydrous(1.9347 mL). The mixture was stirred at ambient temperature for 6 h. Themixture was stirred at 40° C. for 2 h, then at ambient temperatureovernight. The mixture was re-treated with diphenyl phosphorazidate(0.16 mL, 0.741 mmol) and DBU (0.11 mL, 0.741 mmol) and was stirred at40° C. for 2 h then at ambient temperature overnight. The mixture wasdiluted with water (25 mL) and extracted with EtOAc (3×20 mL). Thecombined organics were washed with brine (25 mL), dried over magnesiumsulfate and evaporated to dryness. The crude material was purified bychromatography on SiO₂ (11 g Sfar Amino D; 0-100% EtOAc in heptane) toafford the title compound (36 mg, 24%) as a pale brown solid.Method B: LC-MS (electrospray): m/z=371.3 (M+H)⁺, RT=1.83 min

Example 60:N-(cyclobutylmethyl)-1-[6-[[4-(1H-indazol-4-yl)triazol-1-yl]methyl]-1H-pyrrolo[3,2-c]pyridin-2-yl]methanamine

Step 1: tert-butylN-(cyclobutylmethyl)-N-[[6-[[4-(1-tetrahydropyran-2-ylindazol-4-yl)triazol-1-yl]methyl]-1H-pyrrolo[3,2-c]pyridin-2-yl]methyl]carbamate

A mixture of 4-ethynyl-1-tetrahydropyran-2-yl-indazole (26 mg, 0.117mmol), tert-butylN-[[6-(azidomethyl)-1H-pyrrolo[3,2-c]pyridin-2-yl]methyl]-N-(cyclobutylmethyl)carbamate(36 mg, 0.0972 mmol) (Intermediate 6), copper sulfate (3.1 mg, 0.0194mmol) and sodium ascorbate (21 mg, 0.107 mmol) in DMF (1.1432 mL) andwater (0.2286 mL) was stirred at ambient temperature for 2 h. Themixture was diluted with water and a 3:1 mixture of CHCl₃/IPA. Thelayers were separated. The aqueous layer was extracted with CHCl₃/IPA(3×40 mL). The organic phase was collected using a Telos phaseseparator, evaporated to dryness under reduced pressure. The materialwas purified by SCX (1 g), loading with MeOH, flushing with MeOH theneluting with 2.5 M NH₃.MeOH solution and collecting and concentratingthe latter fractions to afford the title compound (67 mg, 100%) as apale brown solid.Method B: LC-MS (electrospray): m/z=597.4 (M+H)⁺, RT=1.96 min

Step 2:N-(cyclobutylmethyl)-1-[6-[[4-(1H-indazol-4-yl)triazol-1-yl]methyl]-1H-pyrrolo[3,2-c]pyridin-2-yl]methanamine

A solution of tert-butylN-(cyclobutylmethyl)-N-[[6-[[4-(1-tetrahydropyran-2-ylindazol-4-yl)triazol-1-yl]methyl]-1H-pyrrolo[3,2-c]pyridin-2-yl]methyl]carbamate(86%, 67 mg, 0.0966 mmol) in MeOH (0.5 mL) was treated with 4M HCl indioxane (2 mL) and the mixture was stirred at ambient temperatureovernight. The solvent was removed in vacuo. The crude material waspurified by preparative HPLC (Method B) and freeze dried to afford thetitle compound (8.0 mg, 19%) as a white solid.Method C: LC-MS (electrospray): m/z=413.4 (M+H)⁺, RT=2.66 min

Intermediate 7: tert-butyl6-(azidomethyl)-2-[[tert-butoxycarbonyl(cyclobutylmethyl)amino]methyl]indole-1-carboxylate

Step 1: methyl 4-iodo-3-[(2,2,2-trifluoroacetyl)amino]benzoate

A stirred suspension of methyl 3-amino-4-iodobenzoate (5.19 g, 18.7mmol) in DCM (51.9 mL) was treated with (2,2,2-trifluoroacetyl)2,2,2-trifluoroacetate (7.8 mL, 56.0 mmol). The resulting solution wasstirred at ambient temperature overnight. The mixture was concentratedin vacuo to give an off white solid, which was redissolved in DCM (40mL) and passed through a plug of silica in a plastic fritted tube. Thesilica was washed with DCM (450 mL) and the filtrate (˜500 mL) wasconcentrated in vacuo and further dried in a vacuum oven at 45° C. forseveral h to afford the title compound (6.94 g, 98%) as an off whitesolid.Method A: LC-MS (electrospray): m/z=371.9 (M+H)⁺, RT=1.18 min

Step 2: methyl2-[[tert-butoxycarbonyl(cyclobutylmethyl)amino]methyl]-1H-indole-6-carboxylate

A oven-dried three-neck 100 mL RBF equipped with a reflux condenser wasflushed with nitrogen and charged with triphenylphosphane (0.68 g, 2.61mmol), Copper (1) Iodide (0.25 g, 1.30 mmol), tripotassium phosphate(3.74 g, 17.4 mmol), methyl4-iodo-3-[(2,2,2-trifluoroacetyl)amino]benzoate (98%, 3.31 g, 8.69 mmol)and 1,4-Dioxane-Anhydrous (40 mL). A solution of tert-butylN-(cyclobutylmethyl)-N-prop-2-ynyl-carbamate (97%, 2.00 g, 8.69 mmol)(Intermediate 2) in 1,4-Dioxane-Anhydrous (8 mL) was added and theresulting thick suspension was de-oxygenated by passing a flow ofnitrogen for 5 min. The mixture was placed in a pre-heated heating blockat 110° C. and stirred rapidly at this temperature for 7.5 h. Thereaction was allowed to stand at ambient temperature overnight. Themixture was heated to 110° C. for another 3 h the next day. The mixturewas cooled down and concentrated. The resulting brown paste waspartitioned between water (60 mL) and EtOAc (30 mL). The aqueous phasewas extracted with EtOAc (3×30 mL). The combined organic phases werewashed with brine (40 mL). The combined aqueous phases wereback-extracted with EtOAc (20 mL). All the organics were combined, driedon magnesium sulfate and concentrated to give the crude product as abrown solid. Purification was carried out by chromatography on SiO₂(0-70% EtOAc/heptane) (Kp-Sil 50 g cartridge) eluting in a gradient ofEtOAc/heptane (0-100%). The product containing fractions were combinedto afford the title compound (2.29 g, 71%) as a brown solid.Method D: LC-MS (electrospray): m/z=373.3 (M+H)⁺, RT=5.46 min

Step 3: 1-tert-butyl 6-methyl2-({[(tert-butoxy)carbonyl](cyclobutylmethyl)amino}methyl)-1H-indole-1,6-dicarboxylate

In a 250 mL RBF was prepared a solution containing methyl2-[[tert-butoxycarbonyl(cyclobutylmethyl)amino]methyl]-1H-indole-6-carboxylate(2.29 g, 6.15 mmol) in DCM (30 mL). The flask was cooled in an ice bathand a solution containing di-tert-butyl dicarbonate (1.61 g, 7.38 mmol)in DCM (20 mL) was added, followed by N,N-dimethylpyridin-4-amine (75mg, 0.615 mmol). The mixture was warmed to room temperature and stirredfor 30 minutes. The mixture was washed with water (40 mL). The aqueousphase was separated and extracted with DCM (2×20 mL). The combinedorganic phases were washed with brine (20 mL), dried over magnesiumsulfate and concentrated to give the crude product as a brown gum.Purification was carried out by chromatography on SiO₂ (KP-Sil 50 gcartridge) eluting in a gradient of EtOAc/heptane (0-50%). The productcontaining fractions were combined to afford the title compound (2.54 g,86%) as a pale-yellow oil.Method B: LC-MS (electrospray): m/z=473.3 (M+H)⁺, RT=2.44 min

Step 4: tert-butyl2-[[tert-butoxycarbonyl(cyclobutylmethyl)amino]methyl]-6-(hydroxymethyl)indole-1-carboxylate

A 50 mL oven-dried RBF was charged with 1-tert-butyl 6-methyl2-[[tert-butoxycarbonyl(cyclobutylmethyl)amino]methyl]indole-1,6-dicarboxylate(2.54 g, 5.37 mmol), purged with nitrogen and then DCM-Anhydrous (20 mL)was added. The solution was kept under nitrogen and cooled using a dryice/acetone cooling bath. 1 M diisobutylalumane in DCM (6 mL, 6 mmol)was added slowly, with stirring of the substrate solution, and additionof the reagent solution being carried out such that the solution isallowed to run down the side of the reaction flask for pre-cooling. Themixture was stirred at the dry ice/acetone bath temperature for 1 h 20min. 1 M diisobutylalumane in DCM (7.5 mL, 7.5 mmol) was added in asimilar manner to previous. The reaction was stirred at cold bathtemperature for 1 h and 40 min. 1 M diisobutylalumane in DCM (7 mL, 7mmol) was added. The mixture was stirred at cold bath temperature for 1h and 45 min. At cold bath temperature, the reaction was quenched withwater (2 mL). After gas evolution subsided, water was added (4 mL) andthe reaction was allowed to warm up to room temperature. The emulsionformed was diluted with brine (50 mL) and extracted with DCM (3×50 mL).The remaining aqueous phase was diluted with a saturated Rochelle saltsolution (50 mL) (improved phase separation) and extracted with DCM (50mL). After standing overnight the solution was extracted again with DCM(50 mL), diluted with 1M NaOH solution (50 mL) and extracted with DCM(50 mL). The combined organics were dried on magnesium sulfate andconcentrated to give the crude as a foam. Purification was carried outby chromatography on SiO₂ (50 g Kp-Sil cartridge) eluting in a gradientof EtOAc/heptane (0-100%). The product containing fractions werecombined to afford the title compound (1.99 g, 83%) as a yellow oil.Method D: LC-MS (electrospray): m/z=445.3 (M+H)⁺, RT=5.67 min

Step 5: tert-butyl6-(azidomethyl)-2-[[tert-butoxycarbonyl(cyclobutylmethyl)amino]methyl]indole-1-carboxylate

An oven-dried 10 mL RBF was charged with tert-butyl2-[[tert-butoxycarbonyl(cyclobutylmethyl)amino]methyl]-6-(hydroxymethyl)indole-1-carboxylate(100%, 400 mg, 0.900 mmol) and DMF-Anhydrous (5 mL). DBU (269 μL, 1.80mmol) was added and the resulting solution was cooled in an ice bath andstirred. Diphenyl phosphorazidate (388 μL, 1.80 mmol) was added and themixture was stirred, allowing to warm up to room temperature, for 24 h.The mixture was diluted with water (5 mL) and extracted with DCM (2×10mL). The aqueous phase was diluted with brine (20 mL) and extracted withDCM (2×10 mL). The organics were combined, washed with brine (5 mL),dried over magnesium sulfate and concentrated to give the crude as abrown oil. Purification was carried out by chromatography on SiO₂ (Sfarduo silica 25 g cartridge) eluting in a gradient of EtOAc/heptane0-100%. The product containing fractions were combined to afford thetitle compound (377 mg, 83%) as a pale-yellow oil.Method C: LC-MS (electrospray): m/z=470.4 (M+H)⁺, RT=5.44 min

Example 61:N-(cyclobutylmethyl)-1-[6-[[4-(1H-indazol-4-yl)triazol-1-yl]methyl]-1H-pyrrolo[3,2-c]pyridin-2-yl]methanamine

Step 1: tert-butyl2-[[tert-butoxycarbonyl(cyclobutylmethyl)amino]methyl]-6-[[4-(1-tetrahydropyran-2-ylindazol-7-yl)triazol-1-yl]methyl]indole-1-carboxylate

7-ethynyl-1-tetrahydropyran-2-yl-indazole (70 mg, 0.31 mmol)(Intermediate 4), tert-butyl6-(azidomethyl)-2-[[tert-butoxycarbonyl(cyclobutylmethyl)amino]methyl]indole-1-carboxylate(145 mg, 0.31 mmol) (Intermediate 7) and sodium ascorbate (74 mg, 0.37mmol) were combined in DMF (4 mL) and water (1 mL) and CuSO₄ (5 mg, 0.03mmol) was added. The mixture was stirred at ambient temperatureovernight. The mixture was diluted with EtOAc (40 mL) and washed withwater (30 mL) and brine (5×30 mL). The organic layer was dried overNa₂SO₄ and evaporated under vacuum. The residue was purified bychromatography on SiO₂ (10 g Sfar Duo, eluting with EtOAc/heptane0-100%) to afford the title compound (127 mg, 59%) as a pale yellowsolid.Method B: LC-MS (electrospray): m/z=696.5 (M+H)⁺, RT=2.41 min

Step 2:N-(cyclobutylmethyl)-1-[6-[[4-(1H-indazol-4-yl)triazol-1-yl]methyl]-1H-pyrrolo[3,2-c]pyridin-2-yl]methanamine

Tert-butyl2-[[tert-butoxycarbonyl(cyclobutylmethyl)amino]methyl]-6-[[4-(1-tetrahydropyran-2-ylindazol-7-yl)triazol-1-yl]methyl]indole-1-carboxylate(127 mg, 0.18 mmol) was dissolved in MeOH (5 mL) and treated with 4M HClin Dioxane (2 mL). The mixture was incubated at ambient temperature for5 h. The mixture was cooled to room temperature and evaporated undervacuum. The residue was purified by preparative HPLC (Method B) and theproduct-containing fractions combined and evaporated under vacuum toafford of the title compound (30 mg, 40%) as a white solid.Method D: LC-MS (electrospray): m/z=412.3 (M+H)⁺, RT=4.56 min

Example 62:2-[1-[[2-[(cyclobutylmethylamino)methyl]-1H-indol-6-yl]methyl]triazol-4-yl]pyrido[1,2-a]pyrimidin-4-one

Step 1: 2-ethynylpyrido[1,2-a]pyrimidin-4-one

2-chloropyrido[1,2-a]pyrimidin-4-one (700 mg, 3.88 mmol), CuI (74 mg,0.388 mmol), PdCl2dppf (284 mg, 0.388 mmol) and triethylamine (2.6 mL,18.5 mmol) were combined in DMF-Anhydrous (4 mL) in a 20 mL pressurevial and the mixture sparged with nitrogen for 10 mins.Ethynyl(trimethyl)silane (1.6 mL, 11.6 mmol) was added and the mixturewas sparged with nitrogen for a further 5 minutes. The mixture washeated at 100° C. overnight. The mixture was cooled to room temperatureand diluted with saturated NaHCO₃ (aq) (50 mL). The mixture wasextracted with DCM (3×50 mL) and the combined organic extracts werewashed with saturated NaHCO₃ (aq) (100 mL), dried over Na₂SO₄ andevaporated under vacuum. The residue was purified by chromatography onSiO₂ (KP—NH, eluting in 0-50% EtOAc/heptane). The crude material wasre-purified by chromatography on SiO₂ (KP— NH, eluting in 0-50%EtOAc/heptane) to afford the title compound (302 mg, 46%) as a brownsolid.Method B: LC-MS (electrospray): m/z=171.2 (M+H)⁺, RT=1.14 min

Step 2: tert-butyl2-formyl-6-[[4-(4-oxopyrido[1,2-a]pyrimidin-2-yl)triazol-1-yl]methyl]indole-1-carboxylate

The title compound (181 mg, 72%) was prepared in the same manner astert-butyl2-formyl-6-[[4-(1-tetrahydropyran-2-ylindazol-4-yl)triazol-1-yl]methyl]indole-1-carboxylatein Example 52.Method B: LC-MS (electrospray): m/z=471.3 (M+H)⁺, RT=1.65 min

Step 3:2-[1-[[2-[(cyclobutylmethylamino)methyl]-1H-indol-6-yl]methyl]triazol-4-yl]pyrido[1,2-a]pyrimidin-4-one

1-cyclobutylmethanamine (0.073 mL, 0.762 mmol) was added to a solutionof tert-butyl2-formyl-6-[[4-(4-oxopyrido[1,2-a]pyrimidin-2-yl)triazol-1-yl]methyl]indole-1-carboxylate(179 mg, 0.381 mmol) in 1,1,1,3,3,3-Hexafluoro-2-propanol (8 mL), andthe mixture was stirred at room temperature for 30 minutes. NaBH₄ (43mg, 1.14 mmol) was added, followed by a few drops of MeOH. The mixturewas stirred at ambient temperature for 1.5 h. The mixture was quenchedwith MeOH (10 mL) at 0° C. (mild effervescence) and concentrated invacuo. The residue was partitioned between saturated NaHCO₃ (aq) (20 mL)and DCM (20 mL) and the phases separated. The aqueous phase wasextracted with DCM (3×20 mL) and the combined organic phases were driedover Na₂SO₄, filtered and concentrated. The crude material was dilutedwith 4M HCl in dioxane (7 mL) and MeOH (0.5 mL), and the mixture wasstirred at ambient temperature for 2 h. The mixture was re-treated with4M HCl in dioxane (5 mL) and MeOH (1 mL) and the mixture was stirred atambient temperature overnight. The mixture was re-treated with 4M HCl indioxane (3 mL) and MeOH (1 mL) and the mixture was stirred at ambienttemperature for 2 h. The solvent from the mixture was removed in vacuo.The residue was purified by preparative HPLC (Method B) and the pureproduct containing fractions were combined, concentrated in vacuo andfreeze dried overnight to afford the title compound (79 mg, 47%) as awhite solid.Method C: LC-MS (electrospray): m/z=440.4 (M+H)⁺, RT=3.15 min

Example 63:N-(cyclobutylmethyl)-1-[6-[[4-(6-methoxyimidazo[1,5-a]pyridin-8-yl)triazol-1-yl]methyl]-1H-indol-2-yl]methanamine

Step 1: 3-bromo-5-methoxy-pyridine-2-carbonitrile

Sodium methoxide (296 mg, 5.47 mmol) was added to an ice-cooled solutionof 3-bromo-5-fluoropyridine-2-carbonitrile (1000 mg, 4.98 mmol) in MeOH(15 mL). The RM was warmed to room temperature and stirred for 1.5 h.Sodium methoxide (296 mg, 5.47 mmol) was added and the RM was stirred atambient temperature for 1 h, heated to 40° C. for 4 h, then at ambienttemperature over the weekend. Sodium methoxide (150 mg) was added andthe mixture was stirred at 60° C. for 4 h. The mixture was evaporatedunder reduced pressure, water was added, and the mixture was extractedwith ethyl acetate. The combined organic extracts were washed withsaturated brine and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure. The residue was purified bychromatography on SiO₂ (25 g SNAP Duo; 0-100% EtOAc in heptane) to thetitle compound (1130 mg, 106%) as a white powder.Method A: LC-MS (electrospray): m/z=213/215 (M+H)⁺, RT=1.05 min

Step 2: (3-bromo-5-methoxy-2-pyridyl)methanamine

1 M DIBAL in DCM (16 mL, 15.9 mmol) was added to an ice-cooled solutionof 3-bromo-5-methoxy-pyridine-2-carbonitrile (1130 mg, 5.30 mmol) in DCE(11 mL). The mixture was warmed to room temperature and stirred for 16h. The mixture was cooled to 0° C., quenched with saturated NH₄Cl (aq),basified using 2 M NaOH and diluted with DCM. The organic phase wascollected using a Telos phase separator and evaporated to dryness underreduced pressure to afford the title compound (840 mg, 69%) as an orangeoil.Method B: LC-MS (electrospray): m/z=217/219 (M+H)⁺, RT=1.22 min

Step 3: tert-butyl N-[(3-bromo-5-methoxy-2-pyridyl)methyl]carbamate

A mixture of (3-bromo-5-methoxy-2-pyridyl)methanamine (830 mg, 3.82mmol), boc anhydride (1001 mg, 4.59 mmol) and triethylamine (1.3 mL,9.56 mmol) in Acetonitrile (26 mL) was stirred at reflux for 1 h. Themixture was evaporated to dryness, then water was added, and the mixturewas extracted with DCM using a Telos phase separator. The organics wereevaporated to dryness to afford the title compound (1130 mg, 75%) as abrown oil.Method A: LC-MS (electrospray): m/z=317/319 (M+H)⁺, RT=1.20 min

Step 4: 8-bromo-6-methoxy-imidazo[1,5-a]pyridine

A mixture of tert-butyl N-[(3-bromo-5-methoxy-2-pyridyl)methyl]carbamate(500 mg, 1.58 mmol), trimethoxymethane (8.6 mL, 78.8 mmol) and TFA (0.47mL, 6.31 mmol) was stirred at 100° C. for 0.5 h. The mixture wasevaporated to dryness and purified by chromatography on SiO₂ (elutingwith 0-100% EtOAc in heptane, then 10% MeOH in EtOAc) to afford thetitle compound (191 mg, 53%) as a light sticky solid.Method A: LC-MS (electrospray): m/z=227/229 (M+H)⁺, RT=0.80 min

Step 5: 2-(6-methoxyimidazo[1,5-a]pyridin-8-yl)ethynyl-trimethyl-silane

A mixture of 8-bromo-6-methoxy-imidazo[1,5-a]pyridine (790 mg, 3.48mmol), ethynyl(trimethyl)silane (0.98 mL, 6.96 mmol),ethynyl(trimethyl)silane (0.98 mL, 6.96 mmol), PdCl₂(dppf) (255 mg,0.348 mmol)triethylamine (2.4 mL, 17.4 mmol) and CuI (66 mg, 0.348 mmol)in DMF-Anhydrous (5 mL) was stirred at 100° C. for 2 h. The mixture wascooled to room temperature, diluted with EtOAc (25 mL) and filteredthrough Celite. The filtrate was evaporated to dryness and purified bychromatography on SiO₂ (eluting with 0-100% EtOAc in heptane) to affordthe title compound (250 mg, 25%) as a brown oil.Method A: LC-MS (electrospray): m/z=245.1 (M+H)⁺, RT=1.11 min

Step 6: 8-ethynyl-6-methoxy-imidazo[1,5-a]pyridine

Potassium carbonate (163 mg, 1.18 mmol) was added to a solution of2-(6-methoxyimidazo[1,5-a]pyridin-8-yl)ethynyl-trimethyl-silane (90%,160 mg, 0.589 mmol) in MeOH (2.75 mL) at ambient temperature and themixture was stirred at ambient temperature for 1 h. The solvent wasremoved under reduced pressure. 25% IPA in CHCl₃ (30 mL) and water (30mL) were added and the organic phase was collected using a Telos phaseseparator and concentrated under reduced pressure to afford the titlecompound (90 mg, 63%) as a brown oil.Method A: LC-MS (electrospray): m/z=173.1 (M+H)⁺, RT=0.77 min

Step 7: tert-butyl2-[[tert-butoxycarbonyl(cyclobutylmethyl)amino]methyl]-6-[[4-(6-methoxyimidazo[1,5-a]pyridin-8-yl)triazol-1-yl]methyl]indole-1-carboxylate

A mixture of 8-ethynyl-6-methoxy-imidazo[1,5-a]pyridine (70 mg, 0.407mmol), tert-butyl6-(azidomethyl)-2-[[tert-butoxycarbonyl(cyclobutylmethyl)amino]methyl]indole-1-carboxylate(191 mg, 0.407 mmol) (Intermediate 7), CuSO₄ (13 mg, 0.0813 mmol) andsodium ascorbate (89 mg, 0.447 mmol) in DMF (4.5 mL) and water (1 mL)was stirred at ambient temperature overnight. The mixture was dilutedwith water and DCM and the organic phase was collected using a Telosphase separator. The organics were evaporated to dryness under reducedpressure and purified by chromatography on SiO₂ (KP—NH; 0-100% EtOAc inheptane, then 0-20% MeOH in EtOAc) to afford the title compound (120 mg,46%) as an orange solid.Method J: LC-MS (electrospray): m/z=642.5 (M+H)⁺, RT=0.82 min

Step 8:N-(cyclobutylmethyl)-1-[6-[[4-(6-methoxyimidazo[1,5-a]pyridin-8-yl)triazol-1-yl]methyl]-1H-indol-2-yl]methanamine

HCl (4M in dioxane, 0.47 mL, 1.87 mmol) was added to a solution oftert-butyl2-[[tert-butoxycarbonyl(cyclobutylmethyl)amino]methyl]-6-[[4-(6-methoxyimidazo[1,5-a]pyridin-8-yl)triazol-1-yl]methyl]indole-1-carboxylate(120 mg, 0.187 mmol) in DCM (1.2 mL) and the mixture was stirred at roomtemperature for 16 h. The mixture was evaporated to dryness and purifiedby preparative HPLC (Method B). The product-containing fractions werecombined, and the organic solvent removed under reduced pressure. Thesolid formed in the aqueous suspension thus obtained was collected byvacuum filtration and dried under vacuum to afford the title compound(26 mg, 31%) as a white powder.Method C: LC-MS (electrospray): m/z=442.4 (M+H)⁺, RT=3.28 min

Intermediate 8: 1-tert-butyl 2-methyl6-(bromomethyl)-1H-indole-1,2-dicarboxylate

Step 1: 1-tert-butyl 2-methyl 6-methyl-1H-indole-1,2-dicarboxylate

Methyl 6-methyl-1H-indole-2-carboxylate (5.25 g, 27.7 mmol) and DMAP(0.53 g, 4.30 mmol) were combined in Acetonitrile (80 mL) and Boc₂O(7.27 g, 33.3 mmol) was added. The reaction was stirred at ambienttemperature for 10 minutes where upon the colour of the solution hadchanged from colourless to dark orange. The temperature was increased to45° C. and stirred overnight. The mixture was cooled to room temperatureand the solvent removed in vacuo to give an orange solid. The solid wasdissolved in EtOAc (150 mL) and washed with water (100 mL). The layerswere separated, and the aqueous layer extracted with EtOAc (100 mL). Thecombined organic phases were washed with brine (100 mL), dried overNa₂SO₄ and evaporated under vacuum to give the crude material as anorange residue. The residue was purified by chromatography on SiO₂ (100g Kp-Sil, eluting with EtOAc/heptane 0-50%) to afford the title compound(8.20 g, 100%) as an off-white crystalline solid.Method B: LC-MS (electrospray): m/z=290.2 (M+H)⁺, RT=2.01 min

Step 2: 1-tert-butyl 2-methyl 6-(bromomethyl)indole-1,2-dicarboxylate

1-tert-butyl O2-methyl 6-methylindole-1,2-dicarboxylate (5.00 g, 17.3mmol), 1-bromopyrrolidine-2,5-dione (2.92 g, 16.4 mmol) and AIBN (284mg, 1.73 mmol) were combined in DCE (200 mL) and the mixture was stirredat 75° C. for 2 h. The mixture was cooled to room temperature andconcentrated under vacuum. The residue was purified by chromatography onSiO₂ (0-10% EtOAc/heptane, KP-sil, 30 g, done in 2 batches), cleanfractions were combined and concentrated to afford the title compound(4.00 g, 61%) as a colourless oil, which formed a white crystallinesolid upon standing.Method B: LC-MS (electrospray): m/z=368.1/370.1 (M+H)⁺, RT=2.00 min

Intermediate 9: 4-(1H-imidazol-4-yl)-1-tetrahydropyran-2-yl-indazole

Step 1: 4-bromo-1-tetrahydropyran-2-yl-indazole

4-bromo-1H-indazole (6.1 g, 31.0 mmol) and toxic acid monohydrate (589mg, 3.10 mmol) were combined in DCM (100 mL) and 3,4-dihydro-2H-pyran(4.24 mL, 46.4 mmol) was added. The mixture was stirred at ambienttemperature for 3 h. The mixture was quenched with saturated NaHCO₃ (aq)(100 mL) and the mixture stirred vigorously for 5 minutes. The layerswere separated, the aqueous phase was extracted with DCM (2×100 mL) andthe combined organic layers dried over Na₂SO₄ and evaporated undervacuum. The residue was purified by chromatography on SiO₂ (100 gkp-Sil, eluting with EtOAc/heptane 0-100%) to afford the title compound(8.91 g, 96%) as a white solid.Method A: LC-MS (electrospray): m/z=280.9/282.9 (M+H)⁺, RT=1.31 min

Step 2:1-tetrahydropyran-2-yl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazole

4-bromo-1-tetrahydropyran-2-yl-indazole (3 g, 10.7 mmol), potassiumacetate (4.76 g, 48.0 mmol),4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(3.52 g, 13.9 mmol) and PdCl₂(dppf) (391 mg, 0.53 mmol) were combined in1,4-Dioxane (40 mL) and the mixture sparged with nitrogen for 5 minutes.The mixture was heated at 100° C. (external) under nitrogen for 2.5 h.The mixture was cooled to room temperature, diluted with EtOAc (150 mL)and filtered. The residue was rinsed with EtOAc and the combinedfiltrates were washed with sat. NaHCO₃ (aq) (100 mL) and brine (100 mL).The organic layer was dried over Na₂SO₄ and evaporated under vacuum. Theresidue was purified by chromatography on SiO₂ (100 g kp-Sil, elutingwith EtOAc/heptane 0-100%) to afford the title compound (3.21 g, 78 5)as a pale yellow wax.Method A: LC-MS (electrospray): m/z=329.2 (M+H)⁺, RT=1.39 min

Step 3: 4-(1H-imidazol-4-yl)-1-tetrahydropyran-2-yl-indazole

1-(oxan-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole(740 mg, 2.25 mmol), 4-bromo-1H-imidazole (440 mg, 2.93 mmol), Pd(OAc)₂(101 mg, 0.45 mmol), APhos (287 mg, 1.08 mmol) and K₂CO₃ (aq) (1.2Maqueous, 5.6 mL, 6.76 mmol) were combined in 1,4-Dioxane (10 mL) and themixture sparged with nitrogen for 5 mins. The vessel was sealed, and themixture heated at 115° C. (external) for 2.5 h. The mixture was cooledto room temperature and stood overnight. The mixture was diluted withwater (80 mL) and extracted with 3:1 chloroform/isopropanol (3×50 mL).The combined organic extracts were dried over Na₂SO₄ and evaporatedunder vacuum. The residue was purified by (chromatography on SiO₂(kp-NH, eluting with EtOAc/heptane 0-100% followed by MeOH/EtOAc 0-20%)to afford the title compound (371 mg, 58%) as a white solid.Method B: LC-MS (electrospray): m/z=296.2 (M+H)⁺, RT=1.35 min

Example 64:N-(cyclobutylmethyl)-1-[6-[[4-(1H-indazol-4-yl)imidazol-1-yl]methyl]-1H-indol-2-yl]methanamine

Step 1: O1-tert-butyl O2-methyl6-[[4-(1-tetrahydropyran-2-ylindazol-4-yl)imidazol-1-yl]methyl]indole-1,2-dicarboxylate

4-(1H-imidazol-4-yl)-1-tetrahydropyran-2-yl-indazole (370 mg, 1.38 mmol)(Intermediate 9), O1-tert-butyl O2-methyl6-(bromomethyl)indole-1,2-dicarboxylate (508 mg, 1.38 mmol)(Intermediate 8), Cs₂CO₃ (599 mg, 2.76 mmol) and NaI (21 mg, 0.14 mmol)were combined in DMF (10 mL) and the mixture heated at 90° C.(External). The mixture was cooled to room temperature, diluted withEtOAc (50 mL) and washed with sat. NaHCO₃ (aq) (30 mL) and brine (5×30mL). The organic layer was dried over Na₂SO₄ and evaporated undervacuum. The residue was purified by chromatography on SiO₂ (25 g SfarDuo, eluting with EtOAc/heptane 0-100% followed by MeOH/EtOAc 0-20%) toafford the title compound (336 mg, 21%) as a pale orange solid.Method B: LC-MS (electrospray): m/z=556.3 (M+H)⁺, RT=1.89 min

Step 2: tert-butyl2-(hydroxymethyl)-6-[[4-(1-tetrahydropyran-2-ylindazol-4-yl)imidazol-1-yl]methyl]indole-1-carboxylate

O1-tert-butyl O2-methyl6-[[4-(1-tetrahydropyran-2-ylindazol-4-yl)imidazol-1-yl]methyl]indole-1,2-dicarboxylate(336 mg, 0.60 mmol) was dissolved in DCM-Anhydrous (10 mL) and cooled to−40° C. (external). DIBAL (1M in DCM, 1.21 mL, 1.21 mmol) was addeddropwise and the mixture stirred at −40° C. for 1 h. DIBAL (1M in DCM,1.21 mL, 1.21 mmol) was added and the mixture was stirred for 3 h. DIBAL(1M in DCM, 1.21 mL, 1.21 mmol) was added and the mixture was stirredfor 5 h. The mixture was quenched by dropwise addition of MeOH (4 mL)and the mixture stirred under cooling for 5 mins, then allowed to warmto room temperature. The mixture was further diluted with 2M NaOH (aq)(4 mL), then water (10 mL) and the mixture stood overnight. The phaseswere separated, and the aqueous phase extracted with DCM (3×30 mL). Thecombined organic layers were dried over Na₂SO₄ and evaporated undervacuum to afford the title product (343 mg, 45%) as a brown residue,which was used without further purification.Method B: LC-MS (electrospray): m/z=528.3 (M+H)⁺, RT=1.73 min

Step 3: tert-butyl2-formyl-6-[[4-(1-tetrahydropyran-2-ylindazol-4-yl)imidazol-1-yl]methyl]indole-1-carboxylate

tert-butyl2-(hydroxymethyl)-6-[[4-(1-tetrahydropyran-2-ylindazol-4-yl)imidazol-1-yl]methyl]indole-1-carboxylate(343 mg, 0.65 mmol) was dissolved in DCE (10 mL) and MnO₂ (565 mg, 6.50mmol) was added. The mixture was heated at reflux for 1 h. Furtheramounts of MnO₂ (565 mg, 6.50 mmol) added and reflux continued for afurther 2 h. The mixture was cooled to room temperature and filteredthrough a plug of Celite. The residue was rinsed with MeOH and thecombined filtrates evaporated under vacuum to afford the title compound(233 mg, 40%) compound as a pale yellow solid. The Material was useddirectly without purification.Method B: LC-MS (electrospray): m/z=526.3 (M+H)⁺, RT=1.88 min

Step 4:N-(cyclobutylmethyl)-1-[6-[[4-(1H-indazol-4-yl)imidazol-1-yl]methyl]-1H-indol-2-yl]methanamine

tert-butyl2-formyl-6-[[4-(1-tetrahydropyran-2-ylindazol-4-yl)imidazol-1-yl]methyl]indole-1-carboxylate(230 mg, 0.44 mmol) and 1-cyclobutylmethanamine (75 mg, 0.88 mmol) werecombined in 1,1,1,3,3,3-Hexafluoro-2-propanol (5 mL) and the mixtureincubated at ambient temperature for 30 minutes. NaBH₄ (50 mg, 1.31mmol) was added with a few drops MeOH and the mixture stirred briefly atambient temperature. The mixture was quenched with MeOH and the mixtureevaporated under vacuum. The residue was partitioned between saturatedNaHCO₃ (aq) (20 mL) and extracted with DCM (3×30 mL). The combinedorganic extracts were dried over Na₂SO₄ and evaporated under vacuum. Theresidue was redissolved in MeOH (5 mL) and 4M HCl in Dioxane (5 mL) andthe mixture heated at 60° C. (external) for 3 h. The mixture was cooledto room temperature and evaporated under vacuum. The residue was loadedto an SCX-2 cartridge (5 g) and the cartridge rinsed with DCM and MeOH,then eluted with 7M NH₃/MeOH. The basic eluent was evaporated undervacuum. The crude material was purified by preparative HPLC (Method B)and the clean product containing fractions were combined and evaporatedunder vacuum to afford the title compound (19 mg, 11%) as a beige solid.Method D: LC-MS (electrospray): m/z=411.3 (M+H)⁺, RT=4.13 min

Intermediate 10:N′-hydroxy-1-tetrahydropyran-2-yl-indazole-4-carboxamidine

Step 1: 4-bromo-1-tetrahydropyran-2-yl-indazole

4-bromo-1H-indazole (8 g, 40.6 mmol), toxic acid monohydrate (772 mg,4.06 mmol) and 3,4-dihydro-2H-pyran (5.56 mL, 60.9 mmol) were combinedin DCM (80 mL) and the mixture stirred at ambient temperature for 3 h.The mixture was quenched with saturated NaHCO₃ (aq) (80 mL) and stirredvigorously for 5 mins. The phases were separated, the aqueous phase wasextracted with DCM (2×50 mL) and the combined organic layers were driedover Na₂SO₄ and evaporated under vacuum. The residue was purified bychromatography on SiO₂ (350 g Sfar Duo, eluting with EtOAc/heptane0-100%) to afford the title compound (11.16 g, 97%) as a colourless oilwhich solidified on standing to a white wax.Method B: LC-MS (electrospray): m/z=281.1/283.1 (M+H)⁺, RT=1.83 min

Step 2: 1-tetrahydropyran-2-ylindazole-4-carbonitrile

An oven-dried three-neck 25 mL RBF was charged with zinc cyanide (459mg, 3.91 mmol), 4-bromo-1-tetrahydropyran-2-yl-indazole (1.00 g, 3.56mmol), palladium-triphenylphosphane complex (1:4) (206 mg, 0.178 mmol)and DMF-Anhydrous (9 mL). The flask was equipped with a refluxcondenser, the assembly flushed with nitrogen and then the mixture wasde-oxygenated by passing a stream of nitrogen gas for 5 min. The mixturewas placed in a pre-heated heating block at 100° C. and the reaction wasstirred at this temperature for 3 h. The mixture was cooled to roomtemperature and diluted with EtOAc (30 mL) and water (20 mL). Theaqueous phase was extracted with EtOAc (2×30 mL). The combined organicswere washed with brine (10 mL), dried over magnesium sulfate andconcentrated to give a reddish oily solid. Purification was carried outby chromatography on SiO₂ (Sfar silica duo 25 g cartridge) eluting in agradient of EtOAc/heptane (0-100%). The product containing fractionswere combined to afford the title compound (697 mg, 86%) as a whitesolid.Method B: LC-MS (electrospray): m/z=228.3 (M+H)⁺, RT=1.60 min

Step 3: N′-hydroxy-1-tetrahydropyran-2-yl-indazole-4-carboxamidine

1-tetrahydropyran-2-ylindazole-4-carbonitrile (100 mg, 0.440 mmol),Ethanol (5 mL) and 17 M hydroxylamine (50% in water) (0.13 mL, 2.20mmol) were combined and heated under reflux at 80° C. for 3.5 h. Themixture was cooled to room temperature and concentrated. The resultingsolid was washed with water (approx. 5 mL) and air-dried to afford awhite solid. Purification was carried out by chromatography on SiO₂ (10g sfar duo cartridge) eluting in a gradient of EtOAc/heptane 0-100%. Theproduct containing fractions were combined to afford the title compound(93 mg, 77%) as an off-white solid.Method B: LC-MS (electrospray): m/z=261.2 (M+H)⁺, RT=1.26 min

Intermediate 11: 2-(1H-indol-6-yl)acetic acid

Step 1: tert-butyl 6-formylindole-1-carboxylate

1H-indole-6-carbaldehyde (4.52 g, 31.14 mmol), Boc₂O (8.15 g, 37.4 mmol)and DMAP (380 mg, 3.1 1 mmol) were combined in Acetonitrile (50 mL) andthe mixture heated at reflux for 1 h. The mixture was cooled to roomtemperature and evaporated under vacuum. The residue was redissolved inEtOAc (150 mL) and washed with sat. NaHCO₃ (aq) (2×80 mL) and brine (80mL). The organic layer was dried over Na₂SO₄ and evaporated undervacuum. The residue was purified by chromatography on SiO₂ (100 g SfarDuo, eluting with EtOAc/heptane 0-100%) to afford the title compound(7.53 g, 95%) as a pale-yellow solid.Method A: LC-MS (electrospray): m/z=246.0 (M+H)⁺, RT=1.33 min

Step 2: 2-(1H-indol-6-yl)acetonitrile

KOtBu (906 mg, 8.07 mmol) was suspended in THF-Anhydrous (25 mL) andcooled to −55° C. (External). A solution of1-[(isocyanomethyl)sulfonyl]-4-methylbenzene (TosMIC; 946 mg, 4.48 mmol)in THF-Anhydrous (8 mL) was added slowly and the mixture stirred undercooling for 15 mins. A solution of tert-butyl6-formylindole-1-carboxylate (1 g, 4.04 mmol) in THF-Anhydrous (10 mL)was then added dropwise over 15 mins, ensuring temperature <−50° C.,giving a deep yellow solution and the mixture stirred at <−50° C. for 2h. MeOH (50 mL) was added and the mixture heated at reflux for 15 mins.The mixture was cooled to room temperature and evaporated under vacuum.The residue was suspended in water (100 mL) and AcOH (4 mL) andextracted with DCM (3×80 mL). The combined organic extracts were driedover Na₂SO₄ and evaporated under vacuum. The residue was purified bychromatography on SiO₂ (25 g Sfar Duo, eluting with EtOAc/heptane0-100%) to afford the title compound (532 mg, 84%) as an off-whitesolid.

Method A: LC-MS (electrospray): m/z=no ionisation (M+H)⁺, RT=1.05 min

Step 3: 2-(1H-indol-6-yl)acetic acid

A flask was charged with 2-(1H-indol-6-yl)acetonitrile (508 mg, 3.25mmol), IPA (40 mL) and water (40 mL). To the resulting solution wasadded lithium hydroxide (4059 mg, 0.163 mol). The mixture was stirred at75° C. for 25 h, with solids deposited above the solvent level beingoccasionally re-introduced to the reaction. The mixture was cooled in anice bath and neutralised with a 1M HCl solution until the pH was 4-5.The reaction was extracted with a mixture of IPA/CHCl₃ 1:3 (4×50 mL).The combined organics were dried over magnesium sulfate and concentratedto give a pink solid. Purification was carried out by chromatography onSiO₂ (25 g sfar duo) eluting in a gradient of DCM/MeOH 0-33%. Productcontaining fractions were collected to afford the title compound (407mg, 69%) as a yellow solid.Method L: LC-MS (electrospray): m/z=176.0 (M+H)⁺, RT=0.6 min

Intermediate 13: +1-{3-fluorobicyclo[1.1.1]pentan-1-yl}ethan-1-amine

Step 1: 3-fluorobicyclo[1.1.1]pentane-1-carboxylic acid

A 500 mL three-neck flask was charged with Selectfluor (17.02 g, 48.0mmol), bicyclo[1.1.1]pentane-1,3-dicarboxylic acid (3.00 g, 19.2 mmol),silver nitrate (245 mg, 1.44 mmol) and water (96 mL), a small volume ofwhich was used to achieve complete transfer of the silver nitrate. Thereaction was equipped with a reflux condenser connected to an oilbubbler and an immersion thermometer. The reaction was de-oxygenated bypassing a stream of nitrogen gas through the contents for 15 minutes.The reaction was kept under a flow of nitrogen and placed in apre-heated heating block at 65° C. (external). The internal temperatureof the reaction reached 60° C. in approximately 15 min, with gasevolution was observed above 50° C. The temperature control wasadjusted, and the internal temperature stabilised at approximately62-63° C. after another 15 minutes. Stirring was continued at thistemperature for 2.5 h. The reaction was cooled to room temperature andextracted with diethyl ether (4×40 mL). The combined organics were driedover Na₂SO₄ and concentrated under vacuum to a small volume. Theresulting oil was allowed to crystallise. The solids were re-dissolvedin a small amount of diethyl ether (approx 15 mL) resulting in theseparation of a white gel phase. The solution was filtered through aphase separator, dried over Na₂SO₄ and concentrated to give the titlecompound (1.85 g, 70%) as a white solid.Method E: LC-MS (electrospray): m/z=129.2 (M−H)⁻, RT=1.44 min

Step 2: 3-fluoro-N-methoxy-N-methylbicyclo[1.1.1]pentane-1-carboxamide

An oven-dried 25 mL flask was charged with3-fluorobicyclo[1.1.1]pentane-1-carboxylic acid (359 mg, 2.62 mmol),purged with nitrogen and DCE (5 mL) and DMF-Anhydrous (18.032 μL) wereadded resulting in the formation of a clear solution. To the solutionwas slowly added N-methoxymethanamine hydrochloride (1.3 g, 13.1 mmol)resulting in gas evolution. The reaction was stirred at room temperaturefor 4 h and then was cooled in ice. Oxalyl chloride (0.45 mL, 5.24 mmol)was added (further gas evolution) followed by slow addition ofN-ethyl-N-isopropyl-propan-2-amine (4.6 mL, 26.2 mmol) and the reactionwas stirred at room temperature for 24 h. The mixture was diluted withDCM (20 mL) and washed with water (5 mL) and brine (5 mL), dried overNa₂SO₄ and concentrated to give a brown oil (˜1.3 g). The material wasre-dissolved in DCM (25 mL) washed with HCl (1M, 5 mL), water (5 mL) andbrine (5 mL), dried over Na₂SO₄ and concentrated to give a brown oil(700 mg). The material was purified by chromatography on SiO₂ [elutingwith 0-100% EtOAc/heptane] followed by 0-100% MeOH/EtOAc to give thetitle compound (347 mg, 73%) as a yellow oil.Method J: LC-MS (electrospray): m/z=174.2 (M−H)⁻, RT=0.50 min

Step 3: 1-(3-fluoro-1-bicyclo[1.1.1]pentanyl)ethanone

A cooled (0° C.) solution of3-fluoro-N-methoxy-N-methyl-bicyclo[1.1.1]pentane-1-carboxamide (130 mg,0.71 mmol) in THF-Anhydrous (2 mL) was treated slowly with methylmagnesium bromide (1M in THF, 1.1 mL, 1.1 mmol) resulting in theformation of a cloudy solution which was stirred at 0-5° C. for 4 h andthen treated with further methyl magnesium bromide (1M in THF, 1.1 mL,1.1 mmol) and the reaction was stirred for 1 h and then quenched withNH₄Cl (sat., 2 mL) and warmed to room temperature. The mixture wasextracted with diethyl ether (20+10 mL) and the combined organics werefiltered through a bed of Na₂SO₄ and concentrated under vacuum (at roomtemperature) to give the title compound (130 mg, 87%) as a yellow oil.

¹H NMR (400 MHz, DMSO) δ 2.31 (d, J=2.7 Hz, 6H), 2.15 (s, 3H)

Step 4: 1-(3-fluoro-1-bicyclo[1.1.1]pentanyl)ethanamine hydrochloride

A solution of 1-(3-fluoro-1-bicyclo[1.1.1]pentanyl)ethanone (130 mg,0.62 mmol), ammonium acetate (954 mg, 12.4 mmol) and sodiumcyanoborohydride (389 mg, 6.2 mmol) in MeOH (2 mL) was stirred at roomtemperature for 20 h. The mixture was diluted with water (3 mL) andextracted with CHCl₃/IPA (3:1, 3×10 mL). The aqueous phase was saturatedwith sodium chloride and extracted with CHCl₃/IPA (3:1, 10 mL). Thecombined organics were washed with a mixture of water (1 mL) and brine(5 mL) and dried over Na₂SO₄. The resulting solution was cooled using anice bath and treated with HCl (4M in dioxane, 4 mL). The mixture wasallowed to warm up and stirred for 3 h before it was concentrated togive a yellow residue (104 mg). The material was dissolved in ethanol (2mL) and diethyl ether (50 mL) was added. The resulting suspension wasstirred for 5 minutes and filtered to give the title compound (36 mg,33%) as a white solid.Method K: LC-MS (electrospray): m/z=129.95 (M+H)⁺, RT=0.45 min

Intermediate 14: 8-bromoimidazo[1,5-a]pyridine

A mixture of formaldehyde (37%, 16 mL, 0.22 mol) and ammonium acetate(20.7 g, 0.27 mol) in acetic acid (100 mL) was stirred at roomtemperature for 10 minutes before 3-bromopyridine-2-carbaldehyde (5.0 g,26.9 mmol) was added portionwise over 2 h and the mixture was stirred atroom temperature for 3 h. The mixture was partitioned between water (100mL) and DCM (100 mL) and the phases separated. The aqueous phase waswashed with DCM (3×100 mL), and the combined organic phases passedthrough an Isolute phase separator and concentrated under vacuum. Theresidue was purified by chromatography on SiO₂ (eluting with 0-100%EtOAc/heptane) to the title compound (2.51 g, 46%) as an off-whitesolid.Method C: LC-MS (electrospray): m/z=196.9/198.9 (M+H)⁺, RT=2.28 min

Intermediate 15: tert-butyl6-(azidomethyl)-2-({[(tert-butoxy)carbonyl]({3-fluorobicyclo[1.1.1]pentan-1-yl}methyl)amino}methyl)-1H-indole-1-carboxylate

The title compound was prepared from1-{3-fluorobicyclo[1.1.1]pentan-1-yl}methanamine hydrochloride in ananalogous manner to the procedures described for Intermediate 2 andintermediate 7 to give (72 mg, 25%) as a cloudy grey oil.Method J: LC-MS (electrospray): m/z=500.6 (M+H)⁺, RT=1.17 min

Intermediate 16:N-({2-formyl-1H-pyrrolo[3,2-c]pyridin-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

Step 1: 4-Amino-5-bromo-pyridine-2-carbonitrile

To a solution of 4-aminopyridine-2-carbonitrile (3.25 g, 27.3 mmol) inacetic acid (30 mL) and acetonitrile (30 mL) was addedBenzyltrimethylammonium tribromide (10.64 g, 27.3 mmol) and potassiumacetate (5.41 g, 54.6 mmol) at room temperature and the mixture wasstirred for 24 h. The mixture was quenched by addition of Na₂SO₃solution (sat., 2 mL) (colour changed from orange to yellow). Themixture was concentrated to dryness at reduced pressure. The residue waspartitioned between EtOAc (200 mL) and Na₂CO₃ (sat., 100 mL). Theorganic layer was separated, washed with brine (100 mL), dried (Na₂SO₄)and concentrated at reduced pressure. The residue was purified bychromatography on SiO₂ (eluting with 0-50% EtOAc in DCM) to afford thetitle compound (2.15 g, 39%) as beige solid solid.Method C: LC-MS (electrospray): m/z=197.9/199.9 (M+H)⁺, RT=1.85 min

Step 2: 4-amino-5-(3,3-diethoxyprop-1-ynyl)pyridine-2-carbonitrile

A degassed mixture of 4-amino-5-bromo-pyridine-2-carbonitrile (480 mg,2.42 mmol), 3,3-diethoxyprop-1-yne (0.42 mL, 2.91 mmol), triethylamine(5.7 mL, 41.2 mmol), triphenylphosphine (13 mg, 0.049 mmol),PdCl₂(PPh₃)₂ (17 mg, 0.024 mmol) and CuI (9.2 mg, 0.049 mmol) inDMF-Anhydrous (3.1 mL) was stirred at 80° C. for 18 h. More PdCl₂(PPh₃)₂(17 mg, 0.024 mmol) and CuI (9.2 mg, 0.049 mmol) was added and themixture was stirred at 80° C. for 2 h. More 3,3-diethoxypropyne (0.2 mL)was added and the mixture was stirred at 80° C. for 2 h. More3,3-diethoxypropyne (0.4 mL) was added and the mixture was stirred at80° C. for 18 h. The mixture was cooled to room temperature, filtered byvacuum filtration to remove the precipitate and washed with EtOAc (25mL). The organic filtrate was washed with water (25 mL), NaHCO₃ (sat.,3×25 mL) and brine (25 mL) dried over magnesium sulfate. The solidresidue in the filtrate was removed by filtration and the filtrate wasevaporated to dryness under reduced pressure. The crude material waspurified by chromatography on SiO₂ (eluting with 0-50% EtOAc in heptane)to afford the title compound (310 mg, 43%) as a brown solid.Method A: LC-MS (electrospray): m/z=246.1 (M+H)⁺, RT=1.05 min

Step 3: 2-(diethoxymethyl)-1H-pyrrolo[3,2-c]pyridine-6-carbonitrile

Potassium tert-butoxide (235 mg, 2.10 mmol) was added to a solution of4-amino-5-(3,3-diethoxyprop-1-ynyl)pyridine-2-carbonitrile (310 mg, 1.05mmol) in NMP-Anhydrous (3.2 mL), and the mixture was stirred at 60° C.for 2 h. The mixture was partitioned between EtOAc (25 mL) and water (25mL). The organic phase was separated, and the aqueous phase wasextracted with EtOAc (25 mL). The combined organics were washed withbrine (3×30 mL), dried over magnesium sulfate, filtered and evaporatedto dryness to afford the title compound (365 mg, 99%) as a brown oil.Method J: LC-MS (electrospray): m/z=246.2 (M+H)⁺, RT=0.65 min

Step 4: tert-butyl6-cyano-2-(diethoxymethyl)pyrrolo[3,2-c]pyridine-1-carboxylate

Boc anhydride (273 mg, 1.25 mmol) was added to a solution of2-(diethoxymethyl)-1H-pyrrolo[3,2-c]pyridine-6-carbonitrile (365 mg,1.04 mmol) and DMAP (25 mg, 0.2 mmol) in acetonitrile (8 mL) and themixture was stirred at room temperature for 18 h. The mixture wasevaporated to dryness, partitioned between NaHCO₃ (sat., 10 mL), water(20 mL) and extracted with DCM (3×20 mL) using a Telos phase separator.The combined organics were evaporated to dryness and purified bychromatography on SiO₂ (eluting with 0-60% EtOAc in heptane) to affordthe title compound (300 mg, 0.851 mmol, 82%) as a colourless oil.Method A: LC-MS (electrospray): m/z=346.1 (M+H)⁺, RT=1.40 min

Step 5: tert-butyl6-(aminomethyl)-2-(diethoxymethyl)pyrrolo[3,2-c]pyridine-1-carboxylate

A mixture of tert-butyl6-cyano-2-(diethoxymethyl)pyrrolo[3,2-c]pyridine-1-carboxylate (300 mg,0.87 mmol) and Raney nickel (˜51 mg, 0.87 mmol) in ammonia in MeOH (7M,0.87 mL, 6.0 mmol) and ethanol (5.5 mL) was stirred at room temperatureunder a hydrogen atmosphere for 18 h. The catalyst was removed byfiltration and washed with EtOH (50 mL). The filtrate was evaporated todryness to afford the title compound (195 mg, 45%) as a colourless oil.Method A: LC-MS (electrospray): m/z=350.1 (M+H)⁺, RT=0.92 min

Step 6: tert-butyl2-(diethoxymethyl)-6-[[(4-oxopyrido[1,2-a]pyrimidine-2-carbonyl)amino]methyl]pyrrolo[3,2-c]pyridine-1-carboxylate

4-oxopyrido[1,2-a]pyrimidine-2-carboxylic acid Intermediate 1 (116 mg,0.61 mmol) was added to a solution of tert-butyl6-(aminomethyl)-2-(diethoxymethyl)pyrrolo[3,2-c]pyridine-1-carboxylate(190 mg, 0.54 mmol), T3P (50% in EtOAc, 0.39 mL, 0.65 mmol) and DIPEA(0.28 mL, 1.63 mmol) in DMF (2.5 mL) and the mixture was stirred at roomtemperature for 1 h. The mixture was partitioned between EtOAc (25 mL)and water (25 mL). The aqueous phase was basified to ˜pH 10 using NaOH(1M) and the organic phase was collected. The basic aqueous phase wasextracted with EtOAc (2×25 mL). The combined organics were washed withbrine (2×25 mL), dried over magnesium sulfate and evaporated to drynessunder reduced pressure. The crude material was purified bychromatography on SiO₂ (eluting with 0-100% EtOAc in heptane, then 0-20%MeOH in EtOAc) to afford the title compound (250 mg, 43%) as acolourless oil.Method A: LC-MS (electrospray): m/z=522.1 (M+H)⁺, RT=1.01 min

Step 7:N-({2-formyl-1H-pyrrolo[3,2-c]pyridin-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

TFA (2.7 mL, 36.8 mmol) was added to a solution of tert-butyl2-(diethoxymethyl)-6-[[(4-oxopyrido[1,2-a]pyrimidine-2-carbonyl)amino]methyl]pyrrolo[3,2-c]pyridine-1-carboxylate(240 mg, 0.46 mmol) in DCM (2.5 mL) and the mixture was stirred at roomtemperature for 1 h.The mixture was evaporated to dryness and the residue was suspended inwater (2 mL) and basified to ˜pH 10 using NaOH (1M). The aqueous mixturewas evaporated to dryness under reduced pressure. The residue wassuspended in MeCN (5 mL) and the precipitate formed was collected byvacuum filtration, washed with water (3 mL) and dried under vacuum toafford (133 mg, 83%) as a brown solid.Method A: LC-MS (electrospray): m/z=348.0 (M+H)⁺, RT=0.69 min

Intermediate 17: 5-amino-6-bromo-pyridine-3-carbonitrile

N-bromosuccinimide (3287 mg, 18.5 mmol) was added to a solution of5-aminopyridine-3-carbonitrile (2000 mg, 16.8 mmol) in DMF-Anhydrous (20mL) and the mixture was stirred at room temperature for 1 h. The mixturewas diluted with water (100 mL) and extracted with EtOAc (100 mL). Theorganic phase was washed with water (100 mL) and brine (2×100 mL), driedover magnesium sulfate and evaporated to dryness. The crude material waspurified by chromatography on SiO₂ (eluting with 0-100% EtOAc inheptane) to afford the title compound (460 mg, 14%) as a yellow solid.

¹H NMR (500 MHz, DMSO) δ 7.97 (d, J=2.1 Hz, 1H), 7.36 (d, J=2.1 Hz, 1H),6.08 (s, 2H)

Intermediate 18:N-({2-formyl-1H-pyrrolo[3,2-c]pyridin-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

The title compound was prepared from Intermediate 17 in an analogousmanner to Intermediate 16 to give (185 mg, 86%) as a light brown solid.Method A: LC-MS (electrospray): m/z=348.0 (M+H)⁺, RT=0.76 min

Intermediate 19: tert-butyl6-(bromomethyl)-2-[[tert-butoxycarbonyl(cyclobutylmethyl)amino]methyl]indole-1-carboxylate

tert-butyl2-[[tert-butoxycarbonyl(cyclobutylmethyl)amino]methyl]-6-(hydroxymethyl)indole-1-carboxylateIntermediate 7 Step 4 (1 g, 2.25 mmol) and tetrabromomethane (2.24 g,6.75 mmol) were combined in THF (30 mL) and triphenylphosphine (1.77 g,6.75 mmol) was added. Colour change to yellow-orange within 2 minutes,and formation of a precipitate was observed. The mixture was heated at55° C. for 2 h. The mixture was cooled to room temperature filtered andthe residue was washed with THF and the combined filtrates evaporatedunder vacuum. The residue was purified by chromatography on SiO₂(eluting with 0-100% TBME/heptane) to afford the title compound (452 mg,%) as a colourless residue.Method A: LC-MS (electrospray): m/z=529.2/531.2 (M+H)⁺, RT=2.06 min

Intermediate 20: tert-butyl 4-bromoimidazole-1-carboxylate

4-bromo-1H-imidazole (2 g, 13.3 mmol), DMAP (163 mg, 1.33 mmol) andBoc₂O (3.78 g, 17.3 mmol) were combined in THE (20 mL)—gas evolutionnoted—and the mixture was stirred at room temperature for 3 h. Themixture was evaporated under vacuum and the residue was purified bychromatography on SiO₂ (eluting with 0-100% EtOAc/heptane) to afford thetitle compound (3.04 g, 92%) as a colourless oil which solidified onstanding to a white waxy solid.Method B: LC-MS (electrospray): m/z=247.2/249.2 (M+H)⁺, RT=1.60 min

Intermediate 21:N-[(2-formyl-1H-indol-6-yl)methyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxamide

The title compound was prepared from Example 2 Step 3 in a similarmanner to that described for Example 2 Step 4 to give (445 mg, 56%) as apale pink solid.Method B: LC-MS (electrospray): m/z=319.2 (M+H)⁺, RT=1.32 min

Example 66:N-(cyclobutylmethyl)-1-[6-[[3-(1H-indazol-4-yl)-1,2,4-oxadiazol-5-yl]methyl]-1H-indol-2-yl]methanamine

Step 1:2-[2-[[tert-butoxycarbonyl(cyclobutylmethyl)amino]methyl]-1H-indol-6-yl]aceticacid

The title compound (62 mg, 76%) was prepared in the same manner asIntermediate 11, using precursor from Intermediate 7 Step 3.Method C: LC-MS (electrospray): m/z=373.2 (M+H)⁺, RT=3.86 min

Step 2:N-(cyclobutylmethyl)-1-[6-[[3-(1H-indazol-4-yl)-1,2,4-oxadiazol-5-yl]methyl]-1H-indol-2-yl]methanamine

The title compound (7.6 mg, 14%) was prepared in the same manner asExample 64.Method C: LC-MS (electrospray): m/z=413.4 (M+H)⁺, RT=3.71 min

Example 114:N-[(2-{[(1-methylcyclopentyl)amino]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

N-[(2-formyl-1H-indol-6-yl)methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide(70 mg, 0.20 mmol), 1-methylcyclopentanamine hydrochloride (55 mg, 0.40mmol) and triethylamine (83 μL, 0.61 mmol) were combined in1,1,1,3,3,3-Hexafluoro-2-propanol (3 mL) and the mixture was stirred atroom temperature for two days. NaBH₄ (76 mg, 2.02 mmol) was added with afew drops MeOH—gas evolution—and the mixture was stirred briefly. Themixture was quenched with MeOH—gas evolution—and evaporated undervacuum. The residue was suspended in NaHCO₃ (sat., 30 mL) and extractedwith chloroform/isopropanol (3:1, 3×30 mL). The combined organicextracts were dried over Na₂SO₄ and evaporated under vacuum. The residuewas purified by preparative HPLC (Method B) and the cleanproduct-containing fractions combined and evaporated under vacuum toafford the title compound (50 mg, 57%) as a pale yellow solid.Method C: LC-MS (electrospray): m/z=430.7 (M+H)⁺, RT=3.43 min

Example 115:N-{[2-(hydroxymethyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

The title compound was isolated during the purification of Example 114(18 mg, 25%) as an off-white solid.Method C: LC-MS (electrospray): m/z=349.3 (M+H)⁺, RT=2.15 minThe compounds in Table 3 were prepared in the same manner as Example 114using commercial amines or described intermediates.

TABLE 3 LCMS Compound LCMS Retention Mass No Name Structure method timeIon 116 N-[(2-{[(1- cyclobutylcyclo- propyl)amino] methyl}-1H-indol-6-yl)methyl]-4- oxo-4H- pyrido[1,2- a]pyrimidine-2- carboxamide

C 3.83 442.6 117 N-{[2-({[(1- methylcyclobutyl) methyl]amino}methyl)-1H- indol-6- yl]methyl}-4- oxo-4 H- pyrido[1,2- a]pyrimidine-2-carboxamide

C 3.46 430.6 118 4-oxo-N-[(2- {[({spiro[2.3] hexan-5- yl}methyl)amino]methyl}-1H- indol-6- yl)methyl]-4H- pyrido[1,2- a]pyrimidine-2-carboxamide

C 3.46 442.6 119 N-({2-[({[3- (fluoromethyl) bicyclo[1.1.1] pentan-1-yl]methyl}amino) methyl]-1H- indol-6- yl}methyl)-4- oxo-4H- pyrido[1,2-a]pyrimidine-2- carboxamide

C 3.19 460.6 120 N-[(2-{[(1-(3- fluorobicyclo[1.1.1] pentan-1-yl}ethyl)amino] methyl}-1H- indol-6- yl)methyl]-4- oxo-4H- pyrido[1,2-a]pyrimidine-2- carboxamide

C 3.32 460.5

Example 121:N-({2-[(tert-butylamino)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

A suspension of tert butylamine (34 μL, 0.566 mmol) andN-[(2-formyl-1H-indol-6-yl)methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide(100 mg, 0.28 mmol) in DCE (7 mL) was stirred at 60° C. for 65 h andleft standing for a week. The mixture was diluted with ethanol (3 mL)and cautiously treated with NaBH₄ (32 mg, 0.85 mmol)—effervescence—andstirred for 16 h. The mixture was quenched with NaHCO₃ (sat., 5 mL)extracted with DCM (3×5 mL) and the extracts were concentrated undervacuum. The residue was purified by preparative HPLC (Method B) to givea pale gum which was triturated with MeCN to give an off-white solid 28mg. The solid was recrystallized from MeCN, the solid was collected byfiltration, washed with Et₂O and dried under vacuum oven to give thetitle compound (16 mg, 14%) as an off-white solid.Method C: LC-MS (electrospray): m/z=404.5 (M+H)⁺, RT=3.10 min

Example 123:N-{[2-(2-{2-azaspiro[3.3]heptanean-2-yl}ethyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

Step 1: N-(5-cyano-2-iodophenyl)-2,2,2-trifluoroacetamide

3-amino-4-iodobenzonitrile (3.3 g, 13.52 mmol) was dissolved in DCM (40mL) and trifluoroacetic anhydride (5.6 mL, 40.3 mmol) was added in aslow stream and the mixture was stirred at room temperature for 1 h. Themixture was evaporated directly onto silica. The solids were depositedon a short pad of silica (˜5 cm diameter, 5 cm depth) and eluted with0-100% DCM/heptane to afford the title compound (4.3 g, 93%) as a whitesolid.Method B: LC-MS (electrospray): m/z=358.1 (M+H)⁺, RT=0.98 min

Step 2: 2-(2-hydroxyethyl)-1H-indole-6-carbonitrile

N-(5-cyano-2-iodo-phenyl)-2,2,2-trifluoro-acetamide (4.3 g, 12.14 mmol),CuI (231 mg, 1.21 mmol) and PdCl₂(dppf) (888 mg, 1.21 mmol) werecombined in triethylamine (30 mL) and the mixture was sparged withnitrogen for 5 minutes before but-3-yn-1-ol (1.84 mL, 24.3 mmol) wasadded, the mixture further sparged briefly and heated at 70° C. undernitrogen for 2 h. The mixture was cooled to room temperature, dilutedwith EtOAc (200 mL) and washed with NaHCO₃ (sat., 2×100 mL) and brine(100 mL). The organic phase was dried over Na₂SO₄ and evaporated undervacuum. The resultant residue was purified by chromatography on SiO₂(eluting with 0-100% EtOAc/heptane) to afford the title compound (1.7 g,74%) as a beige solid.Method C: LC-MS (electrospray): m/z=187.1 (M+H)⁺, RT=0.65 min

Step 3: 2-(6-cyano-1H-indol-2-yl)ethyl 4-methylbenzene-1-sulfonate

4-Methylbenzenesulfonyl chloride (532 mg, 2.79 mmol) was added to amixture of 2-(2-hydroxyethyl)-1H-indole-6-carbonitrile (400 mg, 2.15mmol) and triethylamine (0.60 mL, 4.30 mmol) in DCM (26 mL) at 0° C. andthe mixture was stirred at 0° C. for 20 minutes and at room temperaturefor 4 h. The mixture was retreated with 4-methylbenzenesulfonyl chloride(532 mg, 2.79 mmol) and was stirred at room temperature for 18 h. Themixture was concentrated under vacuum and the residue was purified bychromatography on SiO₂ to give the title compound (639 mg, 78%) as ayellow oil, which crystallised on standing to an off white solid.Method A: LC-MS (electrospray): m/z=341.1 (M+H)⁺, RT=1.24 min

Step 4:2-[2-(2-azaspiro[3.3]heptanean-2-yl)ethyl]-1H-indole-6-carbonitrile

2-(6-cyano-1H-indol-2-yl)ethyl 4-methylbenzenesulfonate (300 mg, 0.881mmol), 2-azaspiro[3.3]heptane hydrochloride (0.37 mL, 1.32 mmol), sodiumiodide (16 mg, 0.110 mmol) and N-ethyl-N-(propan-2-yl)propan-2-amine(0.31 mL, 1.76 mmol) were combined in DMSO (6.6 mL) and the mixture wasstirred at 50° C. for 3 h. The mixture was cooled to room temperature,diluted with EtOAc (20 mL) and washed with NaHCO₃ (sat., 20 mL). A whiteinsoluble solid was removed by filtration, the layers were separated,and the mixture was extracted with EtOAc (3×20 mL). The organics werewashed with brine (50 mL), dried over MgSO₄, and concentrated undervacuum to a residue which was purified by chromatography on SiO₂(eluting with 0-100% EtOAc/heptane then 0-20% MeOH/EtOAc) to give thetitle compound (62 mg, 19%) as an orange oil.Method A: LC-MS (electrospray): m/z=266.3 (M+H)⁺, RT=0.86 min

Step 5:[2-[2-(2-azaspiro[3.3]heptanean-2-yl)ethyl]-1H-indol-6-yl]methanamine

A mixture of2-[2-(2-azaspiro[3.3]heptanean-2-yl)ethyl]-1H-indole-6-carbonitrile (62mg, 0.23 mmol) and ammonia in MeOH (7M, 0.61 mL, 4.29 mmol) in ethanol(2.4 mL) was degassed, a slurry of Raney-nickel (50%, 123 mg, 1.04 mmol)in H₂O was added, the mixture was degassed further and stirred under ahydrogen atmosphere for 4.5 h. The mixture was retreated withRaney-nickel (50%, 123 mg, 1.04 mmol) degassed and stirred under ahydrogen atmosphere for 16 h. The mixture was filtered through Celite,washing with MeOH (100 mL) and concentrated to give the title compound(44 mg, 50%) as a colourless oil.Method J: LC-MS (electrospray): m/z=270.3 (M+H)⁺, RT=0.69 min

Step 6:N-{[2-(2-{2-azaspiro[3.3]heptanean-2-yl}ethyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

HATU (85 mg, 0.223 mmol) was added to a mixture of4-oxopyrido[1,2-a]pyrimidine-2-carboxylic acid Intermediate 1 (28 mg,0.15 mmol) and DIPEA (0.13 mL, 0.74 mmol) in DMF (0.6 mL), and themixture was stirred at room temperature for 10 minutes.[2-[2-(2-azaspiro[3.3]heptanean-2-yl)ethyl]-1H-indol-6-yl]methanamine(40 mg, 0.148 mmol) was added, and the mixture was stirred at roomtemperature for 90 minutes. The mixture was quenched with NaHCO₃ (sat.,50 mL) and extracted with EtOAc (3×50 mL). The combined organic phaseswere washed with water (50 mL) then brine (50 mL), dried (MgSO₄) andconcentrated under vacuum. The crude material was purified byPreparative HPLC (Method B) to give the title product (4.1 mg, 6.1%) asan off white solid.Method C: LC-MS (electrospray): m/z=442.7 (M+H)⁺, RT=3.45 min

Example 124:({3-fluorobicyclo[1.1.1]pentan-1-yl}methyl)({6-[(4-{imidazo[1,5-a]pyridin-8-yl}-1H-1,2,3-triazol-1-yl)methyl]-1H-indol-2-yl}methyl)amine

The title compound was prepared in an analogous manner to Example 63using intermediates 14 and 15 giving (7 mg, 31%) as a brown solid.Method E: LC-MS (electrospray): m/z=442.2 (M+H)⁺, RT=1.36 min

Example 125:N-[(2-{[({3-fluorobicyclo[1.1.1]pentan-1-yl}methyl)amino]methyl}-1H-indol-6-yl)methyl]-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-7-carboxamide

Step 1: tert-butyl N-{[2-(diethoxymethyl)-1H-indol-6-yl]methyl}carbamate

2-(diethoxymethyl)-1H-indole-6-carbonitrile (Example 2 Step 3) (200 mg,0.82 mmol), Boc anhydride (268 mg, 1.23 mmol) and NiCl₂ (11 mg, 0.08mmol) were combined in MeOH (5 mL) and NaBH₄ (155 mg, 4.10 mmol) wasadded in three portions over 3 mins—strong gas evolution, black colourand the mixture was stirred at room temperature for 30 minutes. FurtherNaBH₄ (155 mg, 4.10 mmol) was added portionwise and the mixture wasstirred for 1 h. The mixture was quenched with NaHCO₃ (sat., 20 mL) andextracted with DCM (3×30 mL). The combined organic extracts were driedover Na₂SO₄ and evaporated under vacuum. The residue was purifiedchromatography on SiO₂ (eluting with 0-100% EtOAc/heptane) to afford thetitle compound (135 mg, 43%) as a yellow residue.Method J: LC-MS (electrospray): m/z=347.5 (M+H)⁺, RT=0.87 min

Step 2: tert-butyl N-[(2-formyl-1H-indol-6-yl)methyl]carbamate

Tert-butyl N-[[2-(diethoxymethyl)-1H-indol-6-yl]methyl]carbamate (135mg, 0.39 mmol) was dissolved in THF (2 mL), water (2 mL) and acetic Acid(2 mL) and stirred at room temperature. The mixture was basified withNaHCO₃ (sat.) and extracted with DCM (3×30 mL). The combined organicextracts were dried over Na₂SO₄ and evaporated under vacuum. The residuewas purified by chromatography on SiO₂ (eluting with 0-100%EtOAc/heptane) to afford the title compound (111 mg, 98%) as a whitesolid.Method J: LC-MS (electrospray): m/z=273.4 (M−H)⁻, RT=0.72 min

Step 3: tert-butylN-[[2-[[(3-fluoro-1-bicyclo[1.1.1]pentanyl)methylamino]methyl]-1H-indol-6-yl]methyl]carbamate

The title compound was prepared using the procedure described forExample 42 to give (92 mg, 67%) as a yellow residue.Method A: LC-MS (electrospray): m/z=374.2 (M−H)⁻, RT=0.93 min

Step 4:[2-[[(3-fluoro-1-bicyclo[1.1.1]pentanyl)methylamino]methyl]-1H-indol-6-yl]methanaminedihydrochloride

The title compound was prepared in a similar fashion to Example 44 Step3 to give 90 mg (quant) as a pink solid.Method A: LC-MS (electrospray): m/z=274.0 (M+H)⁺, RT=0.21 min

Step 5:N-[(2-{[({3-fluorobicyclo[1.1.1]pentan-1-yl}methyl)amino]methyl}-1H-indol-6-yl)methyl]-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-7-carboxamide

5-oxothiazolo[3,2-a]pyrimidine-7-carboxylic acid (56 mg, 0.28 mmol) wasadded to a stirred solution of DIPEA (136 μL, 0.8 mmol) and[2-[[(3-fluoro-1-bicyclo[1.1.1]pentanyl)methylamino]methyl]-1H-indol-6-yl]methanaminedihydrochloride (90 mg, 0.26 mmol) in DMF (2 mL) and the mixture wasleft to stir at room temperature for 10 mins. HATU (108 mg, 0.28 mmol)in DMF (2 mL) was added, and the mixture was stirred at room temperaturefor 2 h. The mixture was partitioned between NaHCO₃ (sat., 25 mL) andEtOAc (25 mL) and the layers separated. The pH of the aqueous layer wasadjusted to pH 11 by addition of NaOH (1M) and the aqueous layer wasextracted with EtOAc (3×25 mL). The combined organic layers were driedover Na₂SO₄ and concentrated under vacuum. The residue was purified bypreparative HPLC (Method B) to give 11 mg of material. The product wasfurther purified by basic preparative HPLC to give the title product(5.2 mg, 8.4%) as a white solid.Method A LC-MS (electrospray): m/z=452.5 (M+H)⁺, RT=3.00 min

Example 126:N-[(2-{[({bicyclo[1.1.1]pentan-1-yl}methyl)amino]methyl}-1H-pyrrolo[3,2-b]pyridin-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

A mixture ofN-[(2-formyl-1H-pyrrolo[3,2-b]pyridin-6-yl)methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide(55 mg, 0.16 mmol), STAB (84 mg, 0.4 mmol) andbicyclo[1.1.1]pentan-1-ylmethanamine hydrochloride (23 mg, 0.17 mmol) inDOE (1.25 ml) was stirred at 50° C. for 1 h. The mixture was evaporatedto dryness, dissolved in DMSO (1 mL), filtered and purified bypreparative HPLC (Method B) to afford the title compound (24 mg, 35%) asa white solid.Method C LC-MS (electrospray): m/z=429.4 (M+H)⁺, RT=2.43 minThe compounds in Table 4 were prepared from either Intermediate 16 orIntermediate 18 in a similar manner to Example 126.

TABLE 4 LCMS Compound LCMS Retention No Name Structure method time MassIon 127 N-[(2-{[({3- fluorobicyclo[1.1.1] pentan-1- yl}methyl)amino]methyl}-1H- pyrrolo[3,2- b]pyridin-6- yl)methyl]-4-oxo- 4H-pyrido[1,2-a]pyrimidine-2- carboxamide

C 2.27 447.4 129 N-[(2-{[({3- methylbicyclo[1.1.1] pentan-1-yl}methyl)amino] methyl}-1H- pyrrolo[3,2- c]pyridin-6- yl)methyl]-4-oxo-4H-pyrido[1,2- a]pyrimidine-2- carboxamide

E 1.08 443.3 130 N-[(2- {[(cyclobutylmethyl) amino]methyl}-1H-pyrrolo[3,2- c]pyridin-6- yl)methyl]-4-oxo- 4H-pyrido[1,2-a]pyrimidine-2- carboxamide

C 2.55 417.4 131 N-[(2- {[({bicyclo[1.1.1] pentan-1- yl}methyl)amino]methyl}-1H- pyrrolo[3,2- c]pyridin-6- yl)methyl]-4-oxo- 4H-pyrido[1,2-a]pyrimidine-2- carboxamide

C 2.64 429.4 132 N-[(2-{[({3- fluorobicyclo[1.1.1] pentan-1-yl}methyl)amino] methyl}-1H- pyrrolo[3,2- c]pyridin-6- yl)methyl]-4-oxo-4H-pyrido[1,2- a]pyrimidine-2- carboxamide

C 2.48 447.5 145 N-((2-((6- azaspiro[3.4]octan- 6-yl)methyl)-1H-pyrrolo[3,2- c]pyridin-6- yl)methyl)-4-oxo- 4H-pyrido[1,2-a]pyrimidine-2- carboxamide

C 3.03 443.4

Example 133:N-[(2-{[(cyclobutylmethyl)amino]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H,6H,7H,8H,9H-pyrido[1,2-a]pyrimidine-2-carboxamide

To a degassed solution ofN-[[2-[(cyclobutylmethylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamideExample 2 (150 mg, 0.350 mmol) in ethanol (25 mL) was added Pd on C (10%Pd (50% wet) 200 mg, 0.188 mmol) at room temperature. The mixture wasdegassed again and stirred under an atmosphere of hydrogen for 6 h. Thecatalyst was removed by filtration (Celite) and washed with ethanol(approximately 20 mL). The filtrate was concentrated at reduced pressureto dryness to afford a yellow oil that was dissolved in MeOH (3 mL) andpurified by preparative HPLC (Method B). The residue was dissolved inacetonitrile (2 mL) and water (2 mL) and lyophilsed to afford the titlecompound (85 mg, 57%) as pale yellow solid.Method C LC-MS (electrospray): m/z=420.5 (M+H)⁺, RT=3.17 min

Example 134:(cyclobutylmethyl)({6-[(4-{1H-pyrrolo[2,3-b]pyridin-5-yl}-1H-imidazol-1-yl)methyl]-1H-indol-2-yl}methyl)amine

Step 1:1-(p-tolylsulfonyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine

5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine(500 mg, 2.05 mmol), DIPEA (714 μl, 4.10 mmol), DMAP (25 mg, 0.20 mmol)and TsCl (469 mg, 2.45 mmol) were combined in DCM (10 mL) and themixture was stirred at room temperature for 20 h. The mixture wasquenched with NaHCO₃ (sat., 20 mL) and the phases separated. The aqueousphase was extracted with DCM (2×20 mL) and the combined organic layerswere dried over Na₂SO₄ and evaporated under vacuum. The residue waspurified by chromatography on SiO₂ (eluting with 0-100% EtOAc/heptane)to afford the title compound (320 mg, 37%) as a white solid.Method B LC-MS (electrospray): m/z=399.2 (M+H)⁺, RT=1.65 min

Step 2: 5-(1H-imidazol-4-yl)-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridine

1-(p-tolylsulfonyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine(320 mg, 0.76 mmol), tert-butyl 4-bromoimidazole-1-carboxylateIntermediate 20 (226 mg, 0.92 mmol) and K₂CO₃ (1.2M aqueous, 1.91 mL,2.29 mmol) were combined in 1,4-Dioxane (5 mL) and the mixture spargedwith nitrogen for 5 minutes. PdCl₂(dppf) (56 mg, 0.08 mmol) was added,the mixture further sparged briefly and the vessel sealed. The mixturewas heated at 100° C. for 2 h. Further tert-butyl4-bromoimidazole-1-carboxylate (120 mg, 0.49 mmol) was added and theheating was continued for 3 h. The mixture was cooled to roomtemperature, diluted with NaHCO₃ (sat., 30 mL) and extracted with DCM(2×30 mL) and chloroform/isopropanol (3:1, 2×30 mL). The combinedorganic extracts were dried over Na₂SO₄ and evaporated under vacuum. Theresidue was purified by chromatography on SiO₂ (kp-NH eluting with0-100% EtOAc/heptane followed by 0-20% MeOH/EtOAc) to afford the titlecompound (163 mg, 57%) as a pale orange solid.Method B LC-MS (electrospray): m/z=339.2 (M+H)⁺, RT=1.44 min

Step 3: tert-butyl2-[[tert-butoxycarbonyl(cyclobutylmethyl)amino]methyl]-6-[[4-[1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-5-yl]imidazol-1-yl]methyl]indole-1-carboxylate

5-(1H-imidazol-4-yl)-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridine (162 mg,0.48 mmol), tert-butyl6-(bromomethyl)-2-[[tert-butoxycarbonyl(cyclobutylmethyl)amino]methyl]indole-1-carboxylateIntermediate 19 (410 mg, 0.81 mmol), K₂CO₃ (199 mg, 1.4 mmol) and sodiumiodide (7 mg, 0.05 mmol) were combined in DMF (8 mL) and the mixture washeated at 80° C. for 6 h. The mixture was cooled to room temperature anddiluted with EtOAc (50 mL) and brine (50 mL). The phases were separated,and the organic phase washed with brine (4×50 mL). The organic layer wasdried over Na₂SO₄ and evaporated under vacuum. The residue was purifiedby chromatography on SiO₂ (eluting with 0-100% EtOAc/heptane followed by0-20% MeOH/EtOAc) to afford the title compound (128 mg, 26%) as a paleyellow solid.Method M LC-MS (electrospray): m/z=765.35 (M+H)⁺, RT=1.79 min

Step 4:(cyclobutylmethyl)({6-[(4-{1H-pyrrolo[2,3-b]pyridin-5-yl}-1H-imidazol-1-yl)methyl]-1H-indol-2-yl}methyl)amine

tert-butyl2-[[tert-butoxycarbonyl(cyclobutylmethyl)amino]methyl]-6-[[4-[1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-5-yl]imidazol-1-yl]methyl]indole-1-carboxylate(120 mg, 0.16 mmol) was dissolved in MeOH (5 mL) and NaOMe (90 mg, 1.67mmol) was added. The vessel was sealed, and the mixture was heated at90° C. for 2 h. The mixture was cooled to room temperature and HCl (4Min Dioxane, 5 mL) was added, and the mixture was stirred at roomtemperature for 4 h. The mixture was evaporated under vacuum. Theresidue was dissolved in MeOH and purified by Ion exchange (SCX-2washing with MeOH and eluting with ammonia in MeoH). The basic eluentwas evaporated under vacuum. The residue was purified by preparativeHPLC (Method B) to afford the title compound (27 mg, 42%) as apale-yellow solid.Method D LC-MS (electrospray): m/z=411.2 (M+H)⁺, RT=4.03 min

Example 135:(cyclobutylmethyl)({6-[(4-{imidazo[1,5-a]pyridin-8-yl}-1H-1,2,3-triazol-1-yl)methyl]-1H-indol-2-yl}methyl)amine

The title compound was prepared in an analogous manner to Example 63using intermediates 7 and 14 giving (192 mg, 74%) as a light yellowsolid.Method C: LC-MS (electrospray): m/z=412.4 (M+H)⁺, RT=3.13 min

Example 136:N-[(2-{[(2,2-dimethylpropyl)amino]methyl}-1H-indol-6-yl)methyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxamide

The title compound was prepared from Intermediate 21 using the proceduredescribed for Example 2 Step 5 to give (30 mg, 23%) as an off-whitesolid.Method C: LC-MS (electrospray): m/z=390.4 (M+H)⁺, RT=3.16 min

Example 137:N-[(2-{[(cyclobutylmethyl)amino]methyl}-1H-indol-6-yl)methyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxamide

The title compound was prepared in the same manner as Example 136 togive (83 mg, 43%) as a white solid.Method C: LC-MS (electrospray): m/z=388.4 (M+H)⁺, RT=2.95 min

Example 138:(cyclobutylmethyl)({6-[(4-{1H-pyrrolo[2,3-b]pyridin-5-yl}-1H-1,2,3-triazol-1-yl)methyl]-1H-indol-2-yl}methyl)amine

Step 1: tert-butyl2-[[tert-butoxycarbonyl(cyclobutylmethyl)amino]methyl]-6-[[4-(1H-pyrrolo[2,3-b]pyridin-5-yl)triazol-1-yl]methyl]indole-1-carboxylate

Under a nitrogen atmosphere, 1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde(60 mg, 0.411 mmol) was suspended in MeOH (dry, 1 mL) and THF (dry 1mL), dimethyl (1-diazo-2-oxopropyl)phosphonate (0.12 mL, 0.821 mmol) andpotassium carbonate (170 mg, 1.23 mmol) were added and the mixture wasstirred at room for 3 h. Tert-Butyl6-(azidomethyl)-2-[[tert-butoxycarbonyl(cyclobutylmethyl)amino]methyl]indole-1-carboxylateIntermediate 7 (193 mg, 0.411 mmol) and copper (1) iodide (16 mg, 0.0821mmol) were added and the mixture was stirred at room temperature for 2h. The mixture was diluted with water and extracted with DCM using aTelos phase separator. The organics were evaporated to dryness andpurified by chromatography on SiO₂ (eluting with 0-60% EtOAc in heptane)to provide the title compound (90 mg, 36%) as a white solid.Method B: LC-MS (electrospray): m/z=612.4 (M+H)⁺, RT=2.15 min

Step 2:(cyclobutylmethyl)({6-[(4-{1H-pyrrolo[2,3-b]pyridin-5-yl}-1H-1,2,3-triazol-1-yl)methyl]-1H-indol-2-yl}methyl)amine

HCl in dioxane (4M in dioxane, 1 mL) was added to a solution oftert-butyl2-[[tert-butoxycarbonyl(cyclobutylmethyl)amino]methyl]-6-[[4-(1H-pyrrolo[2,3-b]pyridin-5-yl)triazol-1-yl]methyl]indole-1-carboxylate(60 mg, 0.09 mmol) in MeOH (1 mL) and the mixture was stirred at 60° C.for 3 h. The mixture was evaporated to dryness and purified bypreparative HPLC (Method B) to afford the title compound (19 mg, 44%) asa white solid.Method C: LC-MS (electrospray): m/z=412.4 (M+H)⁺, RT=3.18 min

Intermediate 22: 8-bromoimidazo[1,5-a]pyridine

A mixture of formaldehyde (37%, 16 mL, 0.22 mol) and ammonium acetate(20.7 g, 0.27 mol) in acetic acid (100 mL) was stirred at roomtemperature for 10 minutes before 3-bromopyridine-2-carbaldehyde (5.0 g,26.9 mmol) was added portionwise over 2 h and the mixture was stirred atroom temperature for 3 h.

Intermediate 23: 8-ethynylimidazo[1,5-a]pyridine

The title compound was prepared from Intermediate 22 using theprocedures described in Example 63 steps 5 and 6 giving (1.29 g, 84%) asa brown solid.Method C: LC-MS (electrospray): m/z=285.2 (2M+H)⁺, RT=2.01 min

Example 140:N-[(3-fluoro-1-bicyclo[1.1.1]pentanyl)methyl]-1-[6-[(4-imidazo[1,5-a]pyridin-8-yltriazol-1-yl)methyl]-1H-pyrrolo[3,2-c]pyridin-2-yl]methanamine

Step 1: 2-bromo-5-iodopyridin-4-amine

To a stirred solution of 2-bromopyridin-4-amine (25 g, 144.5 mmol) inacetonitrile (500 mL) was added N-iodosuccinimide (39.01 g, 173.4 mmol).The resulting reaction mixture was stirred at 80° C. for 16 h. Thereaction was repeated in the same manner and combined for work up. Thereaction was cooled to room temperature and concentrated under vacuum.The residue was dissolved in saturated solution of sodium thiosulfate(700 mL) and extracted with ethyl acetate (250 mL×3). The combinedorganic layers were dried over anhydrous Na₂SO₄ and concentrated undervacuum. The crude product was purified by chromatography on SiO₂(eluting with 5% ethyl acetate in hexane) to afford the title compound(37 g 80%) as a yellow solid.

¹H NMR: (400 MHz, DMSO-d6) δ 8.16 (s, 1H), 6.77 (s, 1H), 6.50 (bs, 2H).LCMS: 3.709 min

Step 2: 2-bromo-5-(3,3-diethoxyprop-1-yn-1-yl) pyridin-4-amine

To a stirred solution of 2-bromo-5-iodopyridin-4-amine (18.5 g, 62.0mmol) in THE (185 mL) were added triethyl amine (152.6 mL, 1086.4 mmol),triphenyl phosphine (0.32 g, 1.2 mmol) and PdCl₂(PPh₃)₂ (0.43 g, 0.62mmol) at room temperature. The solution was de-gassed by bubblingnitrogen gas into the solution for 0.5 h. Then copper (I) iodide (0.23g, 1.2 mmol) and 3,3-Diethoxyprop-1-yne (11.9 g, 93.1 mmol) were addedand the reaction was stirred at 60° C. for 16 h. The reaction wasrepeated in the same manner and combined for work up. The reaction wascooled to room temperature and poured into saturated sodium bicarbonate(700 mL). The aqueous layer was extracted with ethyl acetate (250 mL×3).The combined organic layers were dried over anhydrous Na₂SO₄ andconcentrated under vacuum. The crude product was purified bychromatography on SiO₂ (eluting with 12% ethyl acetate in hexane) toafford the title compound (33.5 g) as a brown solid.

¹H NMR: (400 MHz, CDCl₃) δ 8.14 (s, 1H), 6.78 (s, 1H), 5.52 (s, 1H),4.82 (bs, 2H), 3.85-3.77 (m, 2H), 3.71-3.64 (m, 2H), 1.29 (t, J=6.8 Hz,6H).

Step 3: 2-(dimethoxymethyl)-1H-pyrrolo[3,2-c]pyridine-6-carbaldehyde

To a solution of 2-bromo-5-(3,3-diethoxyprop-1-yn-1-yl)pyridin-4-amine(16.5 g, 5.53 mmol) in NMP (165 mL) was added potassium tert-butoxide(12.42 g, 110.7 mmol). The reaction mixture was allowed to stir at 50°C. for 3 h. The reaction was repeated in the same manner and combinedfor work up. The reaction was cooled to room temperature and poured intocold water (500 mL). The aqueous layer was extracted with diethyl ether(250 mL×3). The combined organic layers were dried over anhydrous Na₂SO₄and concentrated under vacuum to afford the title compound (35.0 g) as ayellow liquid.

¹H NMR: (400 MHz, CDCl₃) δ 8.78 (bs, 1H), 8.66 (s, 1H), 7.50 (s, 1H),6.60 (s, 1H), 5.74 (s, 1H), 3.73-3.58 (m, 4H), 1.28 (t, J=7.2 Hz, 6H).

Sodium hydride (60%, 590 mg, 14.8 mmol) was added to an ice-cooledsolution of 6-bromo-2-(dimethoxymethyl)-1H-pyrrolo[3,2-c]pyridine (1000mg, 3.69 mmol) in THF-Anhydrous (32.5 mL) and the mixture was stirredunder ice-cooling for 10 minutes. The mixture was cooled to −78° C. andt-BuLi (1.9M in pentane, 10 mL, 18.4 mmol) was added and the mixture wasstirred at −78° C. for 1 h. Anhydrous DMF (1714 μL, 22.1 mmol) was addedand the mixture was stirred at −78° C. for 45 minutes. The mixture wasthen quenched with saturated NH₄Cl (sat., 30 mL) and extracted withEtOAc (3×30 mL). The combined organic layers were washed with brine(2×40 mL), dried over MgSO₄, and concentrated under reduced pressure.The residue was purified by chromatography on SiO₂ (eluting with 20-100%EtOAc in heptane) to afford (650 mg, 78%) as a white solid.Method C: LC-MS (electrospray): m/z=221.1 (M+H)⁺, RT=1.84 min

Step 4: tert-butyl2-(dimethoxymethyl)-6-formyl-pyrrolo[3,2-c]pyridine-1-carboxylate

Boc anhydride (750 mg, 3.44 mmol) was added to a solution of2-(dimethoxymethyl)-1H-pyrrolo[3,2-c]pyridine-6-carbaldehyde (650 mg,2.86 mmol) and DMAP (70 mg, 0.573 mmol) in acetonitrile (21 mL) and themixture was stirred at room temperature for 1 h. The mixture wasevaporated to dryness, partitioned between NaHCO₃ (sat., 10 mL)/water(20 mL) and extracted with DCM (3×20 mL) using a Telos phase separator.The organics were evaporated to dryness and purified by chromatographyon SiO₂ (eluting with 0-60% EtOAc in heptane) to afford (790 mg, 77%) asa colourless oil that solidified upon scratching to a white solid.Method A: LC-MS (electrospray): m/z=321.0 (M+H)⁺, RT=1.14 min

Step 5: tert-butyl2-(dimethoxymethyl)-6-(hydroxymethyl)pyrrolo[3,2-c]pyridine-1-carboxylate

NaBH₄ (71 mg, 1.87 mmol) was added to an ice-cooled solution oftert-butyl2-(dimethoxymethyl)-6-formyl-pyrrolo[3,2-c]pyridine-1-carboxylate (500mg, 1.56 mmol) in MeOH (16 mL) and the mixture was stirred for 15minutes. The mixture was quenched with water (5 mL) and extracted withDCM (3×10 mL) using a Telos phase separator. The organic phase wasevaporated to dryness to afford the title compound (380 mg, 73%) as acolourless oil that solidified upon scratching to a white solid.Method A: LC-MS (electrospray): m/z=323.0 (M+H)⁺, RT=0.87 min

Step 6: tert-butyl6-(azidomethyl)-2-(dimethoxymethyl)pyrrolo[3,2-c]pyridine-1-carboxylate

To a stirring solution of tert-butyl2-(dimethoxymethyl)-6-(hydroxymethyl)pyrrolo[3,2-c]pyridine-1-carboxylate(390 mg, 1.14 mmol) and DBU (339 μL, 2.27 mmol) in DMF-Anhydrous (6.7mL) under N₂ at 0° C. was added dropwise DPPA (489 μL, 2.27 mmol) andthe mixture was stirred at room temperature for 72 h. The mixture wasdiluted with water (30 mL) and extracted with EtOAc (5×10 mL). Theorganics were washed with brine (10 mL), dried (MgSO₄) and concentratedto a pink oil. The crude was purified by chromatography on SiO₂ (elutingwith 0%-100% EtOAc in heptane) to afford the title compound (394 mg,99%) as a colourless oil.

Method J: LC-MS (electrospray): m/z=348.4 (M+H)⁺, RT=0.88 min

Step 7: 6-(azidomethyl)-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde

A solution of tert-butyl6-(azidomethyl)-2-(dimethoxymethyl)pyrrolo[3,2-c]pyridine-1-carboxylate(100 mg, 0.29 mmol) in THF (2 mL), water (2 mL) was stirred at roomtemperature. Acetic acid (2 mL) was added and stirring was continued fora further 2 h. The mixture was then stirred at 50° C. for 16 h. Thereaction was vigorously concentrated, and the residue was diluted withNaHCO₃ (sat., 15 mL) and extracted with IPA:CHCl₃ (1:3, 4×10 mL). Theorganics were dried (MgSO₄) and concentrated to give the title compound(94 mg, quant) as a beige solid.Method J: LC-MS (electrospray): m/z=204.2 (M+H)⁺, RT=0.63 min

Step 8:1-[6-(azidomethyl)-1H-pyrrolo[3,2-c]pyridin-2-yl]-N-[(3-fluoro-1-bicyclo[1.1.1]pentanyl)methyl]methanamine

A solution of {3-fluorobicyclo[1.1.1]pentan-1-yl}methanaminehydrochloride (65 mg, 0.43 mmol),6-(azidomethyl)-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde (94 mg, 0.29mmol), STAB (362 mg, 1.71 mmol) and N-ethyl-N-isopropyl-propan-2-amine(0.15 mL, 0.86 mmol) in DCE (6 mL) under N₂ was stirred at 60° C. for 2h. The mixture was diluted with NaHCO₃ (sat., 15 mL) and extracted withIPA:CHCl₃ (1:3, 5×5 mL). The organics were dried (MgSO₄) andconcentrated to a yellow oil (0.3 g). The crude was purified bychromatography on SiO₂ (eluting with 15%-100% EtOAc in heptane then0-12% MeOH in EtOAc) to afford the title compound (81 mg, 71%) as acolourless oil.Method J: LC-MS (electrospray): m/z=301.3 (M+H)⁺, RT=0.63 min

Step 9:N-[(3-fluoro-1-bicyclo[1.1.1]pentanyl)methyl]-1-[6-[(4-imidazo[1,5-a]pyridin-8-yltriazol-1-yl)methyl]-1H-pyrrolo[3,2-c]pyridin-2-yl]methanamine

A solution of1-[6-(azidomethyl)-1H-pyrrolo[3,2-c]pyridin-2-yl]-N-[(3-fluoro-1-bicyclo[1.1.1]pentanyl)methyl]methanamine(81 mg, 0.202 mmol) and 8-ethynylimidazo[1,5-a]pyridine Intermediate 23(29 mg, 0.202 mmol) in DMF (1.7 mL) and water (0.6 mL) at roomtemperature was treated with sodium ascorbate (44 mg, 0.223 mmol) andCuSO₄ (7 mg, 0.041 mmol) and stirred at room temperature for 1 h. Themixture was concentrated and purified by preparative HPLC (Method B).The product containing fractions were concentrated gently to remove theMeCN and the remaining aqueous was extracted with IPA:CHCl₃ (1:3, 4×10mL). The organics were dried (MgSO₄) and concentrated to a residue whichwas purified by acidic reverse-phase chromatography (Biotage IsoleraFour; 6 g Sfar Duo C18-D; 10%-100% MeCN (0.1% formic acid) in water(0.1% formic acid)). The product fractions were basified using NaHCO₃(sat, 5 mL) and concentrated to remove the MeCN, the remaining aqueouswas extracted with IPA:CHCl₃ (1:4, 5×5 mL). The organics were dried(MgSO₄) and concentrated to give the title compound (11 mg, 12%) as anoff-white solid.Method C: LC-MS (electrospray): m/z=443.4 (M+H)⁺, RT=2.49 min

Intermediate 25: 4-azido-1-(oxan-2-yl)-1H-indazole

Step 1: 1H-indazol-4-amine

To a solution of 4-nitro-1H-indazole (50.0 g, 153.33 mmol) in MeOH (500mL) was added Pd/C (50% wet) (10%, 5.00 g) at room temperature. Thereaction mixture was placed under an atmosphere of hydrogen and stirredat room temperature for 5 h. The reaction mixture was filtered throughcelite pad and washed with additional MeOH (3×200 mL). The combinedfiltrate was concentrated under vacuum to afford the title compound(14.0 g, 34%).Method G: LC-MS (electrospray): m/z=134.0 (M+H)⁺, RT=0.49 min

Step 2: 4-azido-1H-indazole

To a solution of 1H-indazol-4-amine (0.50 g, 3.14 mmol) in acetonitrile(5 mL) was added tert butyl nitrite (1.16 g, 12.57 mmol) followed byaddition of sodium azide (0.97 g, 15.7 mmol) at 0° C. The resultingreaction mixture was stirred at 60° C. for 16 h. The reaction mixturewas cooled to room temperature. This procedure was repeated five timesand the combined reactions were poured into water (250 mL). The mixturewas extracted with ethyl acetate (3×100 mL). The combined organic layerswere dried (Na₂SO₄) and concentrated under vacuum. The crude materialwas purified by chromatography on SiO₂ (60-120) eluting with 15% EtOAcin hexane to afford the title compound (0.90 g, 25%). LCMS: 1.504 min,MS: ES+160.1 (M+1);Method G: LC-MS (electrospray): m/z=160.1 (M+H)⁺, RT=1.50 min

Step 3: 4-azido-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

To a solution of 4-azido-1H-indazole (1.0 g, 6.3 mmol) in EtOAc (10 mL)was added dihydropyran (1.30 g, 15.5 mmol) followed by TFA (0.07 g, 0.63mmol) at 0° C. and the resulting reaction mixture was stirred at 70° C.temperature for 4 h. The reaction mixture was allowed to cool to roomtemperature, poured into saturated NaHCO₃ (sat, 100 mL) and extractedwith ethyl acetate (2×50 mL). The organic layer was dried (Na₂SO₄) andconcentrated under vacuum. The crude material was purified bychromatography on SiO₂ (60-120) eluting with 8% EtOAc in hexane toafford the title compound (0.9 g, 59%).Method G: LC-MS (electrospray): m/z=244.1 (M+H)⁺, RT=2.07 min

Intermediate 26: tert-butyl2-(((tert-butoxycarbonyl)(cyclobutylmethyl)amino)methyl)-6-(prop-2-yn-1-yl)-1H-indole-1-carboxylate

Step 1: 1-(6-bromo-1H-indol-2-yl)-N-(cyclobutylmethyl)methanamine

To a stirred solution of 6-bromo-1H-indole-2-carbaldehyde (4.00 g, 17.80mmol) and cyclobutylmethylamine (3.04 g, 35.70 mmol) in DCE/MeOH (200mL, 4:1) was added sodium triacetoxy borohydride (11.32 g, 53.40 mmol)portionwise at 0° C. The resulting solution was then stirred at roomtemperature for 16 h. The reaction was repeated in the same manner andcombined for work up. The reaction was poured into water (100 mL) andthe aqueous layer was extracted with dichloromethane (70 mL×3). Thecombined organic layers were dried over anhydrous Na₂SO₄ andconcentrated under vacuum. The crude product was purified bychromatography on SiO₂ (eluting with 2.2% MeOH in DCM) to afford thetitle compound (7.0 g).

¹H-NMR (400 MHz, DMSO-d₆) δ 11.12 (s, 1H), 7.49 (s, 1H), 7.39 (d, J=8.4Hz, 1H), 7.05 (dd, J=8.4, 2.0 Hz, 1H), 6.28 (s, 1H), 3.79 (s, 2H),2.45-2.37 (m, 1H), 2.02-1.94 (m, 2H), 1.91 (s, 2H), 1.86-1.75 (m, 2H),1.68-1.58 (m, 2H).

Step 2: tert-butyl6-bromo-2-(((tert-butoxycarbonyl)(cyclobutylmethyl)amino)methyl)-1H-indole-1-carboxylate

To a stirred solution of1-(6-bromo-1H-indol-2-yl)-N-(cyclobutylmethyl)methanamine (4.00 g, 13.60mmol) in THF (50 mL) was added LiHMDS in (1M in THF, 41.00 mL, 41.00mmol) followed by the addition of Boc-anhydride (11.87 g, 54.40 mmol) atroom temperature. The mixture was heated at 70° C. for 16 h, cooled toroom temperature and poured into water (100 mL). The aqueous layer wasextracted with ethyl acetate (50 mL×3). The combined organic layers weredried over anhydrous Na₂SO₄ and concentrated under vacuum. The crudeproduct was purified by chromatography on SiO₂ (eluting with 8% ethylacetate in hexane) to afford the title compound (5.0 g, 30%).Method LC04_ABF3: LC-MS (electrospray): m/z=493.6/495.6 (M+H)⁺, RT=2.81minMS (ESI-MS): m/z calcd for C₂₄H₃₃BrN₂O₄[MH]+492.16, found 493.63 &495.63 [M+1 & M+3].

Step 3: tert-butyl2-(((tert-butoxycarbonyl)(cyclobutylmethyl)amino)methyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-1-carboxylate

To a stirred solution of tert-butyl6-bromo-2-(((tert-butoxycarbonyl)(cyclobutylmethyl)amino)methyl)-1H-indole-1-carboxylate(5.00 g, 10.16 mmol), in 1,4-dioxane (50 mL) were added potassiumacetate (3.00 g, 30.40 mmol) and bispinacolatediborane (10.32 g, 40.60mmol). The solution was de-gassed by bubbling nitrogen gas into thesolution for 0.5 h and PdCl₂(dppf) (0.740 g, 1.01 mmol) was added atroom temperature. The resulting reaction mixture was heated at 90° C.for 2 h, cooled to room temperature and poured into water (50 mL). Theaqueous layer was extracted with ethyl acetate (50 mL×3). The combinedorganic layers were dried over anhydrous Na₂SO₄ and concentrated undervacuum. The crude product was purified by chromatography on SiO₂(eluting with 10% ethyl acetate in hexane) to afford the title compound(5.0 g, 92%).Method LC04-ABR2: LC-MS (electrospray): m/z=542.18 (M+H)⁺, RT=3.42 minMS (ESI-MS): m/z calcd for C₃₀H₄₅BN₂O₆[MH]+540.34, found 542.18 [M+1].

Step 4: tert-butyl 2-(((tert-butoxycarbonyl) (cyclobutylmethyl) amino)methyl)-6-(3-(trimethylsilyl) prop-2-yn-1-yl)-1H-indole-1-carboxylate

To a stirred mixture of tert-butyl2-(((tert-butoxycarbonyl)(cyclobutylmethyl)amino)methyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-1-carboxylate(5.00 g, 9.25 mmol) in 1,4-dioxane (50 mL) & water (2.5 mL) were addedpotassium carbonate (3.84 g, 27.70 mmol) and3-bromo-1-(trimethylsilyl)-1-propyne (5.30 g, 27.70 mmol). The solutionwas de-gassed by bubbling nitrogen gas into the solution for 0.5 h andPdCl₂(dppf) (0.680 g, 0.92 mmol) was added at room temperature. Thereaction was heated at 80° C. for 5 h, cooled to room temperature andpoured into water (50 mL). The aqueous layer was extracted with ethylacetate (50 mL×3). The combined organic layers were dried over anhydrousNa₂SO₄, filtered and concentrated under vacuum. The crude product waspurified by column chromatography on SiO₂ (eluting with 60% ethylacetate in hexane) to afford the title compound (1.2 g, 24%). 1H NMR:(400 MHz, dmso-d₆) 8.10 (s, 1H), 7.49 (d, J=8.4 Hz, 1H), 7.13 (d, J=8.0Hz, 1H), 6.26 (s, 1H), 4.66 (s, 2H), 3.81 (s, 2H), 1.99-1.90 (m, 2H),1.82-1.76 (m, 2H), 1.70-1.66 (m, 10H), 1.47 (s, 9H), 0.16 (s, 9H).

Step 5: tert-butyl2-(((tert-butoxycarbonyl)(cyclobutylmethyl)amino)methyl)-6-(prop-2-yn-1-yl)-1H-indole-1-carboxylate

To a stirred solution of tert-butyl2-(((tert-butoxycarbonyl)(cyclobutylmethyl)amino)methyl)-6-(3-(trimethylsilyl)prop-2-yn-1-yl)-1H-indole-1-carboxylate(3.00 g, 5.70 mmol) in THF (20 mL) was added TBAF (1M in THF, 5.70 mL,5.70 mmol) at 0° C. The reaction was stirred at 0° C. for 30 min. beforebeing poured into water (30 mL) and extracted with ethyl acetate (50mL×3). The combined organic layers were dried over anhydrous Na₂SO₄ andconcentrated under vacuum to afford the title compound (1.5 g, 57%).Method LC03_ABR2: LC-MS (electrospray): m/z=493.6/495.6 (M+H)⁺, RT=3.27minMS (ESI-MS): m/z calcd for C₂₇H₃₆N₂O₄[MH]+452.27, found 453.91 [M+1].(LCMS: 90.21%, rt: 3.27 min).

Intermediate 27: tert-butyl 2-(tert-butoxycarbonyl)((3,3-difluorocyclobutyl) methyl) amino)methyl)-6-(prop-2-yn-1-yl)-1H-indole-1-carboxylate

The title compound was prepared from1-(3,3-difluorocyclobutyl)methanamine in the same manner as Intermediate26 to afford the title compound (0.36 g, 69%).

¹H NMR: (DMSO-d₆, 400 MHz) δ 8.10 (s, 1H), 7.48 (d, J=7.6 Hz, 1H), 7.13(d, J=7.6 Hz, 1H), 6.26 (s, 1H), 4.69 (br s, 2H), 3.75 (br s, 2H), 3.43(d, J=6.4 Hz, 3H), 3.12 (d, J=2.0 Hz, 1H), 2.66-2.32 (m, 4H), 1.65 (s,9H) 1.44 (s, 9H) Intermediate 28:

Step 1: tert-butyl (2-chloropyridin-3-yl) carbamate

To a stirred solution of 2-chloropyridin-3-amine (10.00 g, 78.00 mmol)in DCM (50 mL) were added Et₃N (23.7 mL, 234.0 mmol), Boc anhydride(25.5 g, 117.0 mmol) and DMAP (0.95 g, 7.8 mmol) at room temperature.The resulting reaction mixture was stirred at room temperature for 16 h.The reaction mixture was poured in to water (100 mL) and the aqueouslayer was extracted with dichloromethane (100 mL×3). The combinedorganic layers were dried over anhydrous Na₂SO₄ and concentrated undervacuum. The crude product was purified by chromatography on SiO₂(eluting with 11% ethyl acetate in hexane) to afford the title compound(8.5 g, 47%).

MS (ESI-MS): m/z calcd for C₁₀H₁₃ClN₂O₂[MH]+228.07, found 229.1 & 231.1[M+1 & M+3].

Step 2: tert-butyl (2-cyanopyridin-3-yl)carbamate

To a solution of tert-butyl (2-chloropyridin-3-yl)carbamate (8.50 g,37.10 mmol) in DMF (50 mL) were added zinc dust (0.29 g, 4.40 mmol) andzinc cyanide (2.61 g, 22.20 mmol). The solution was de-gassed bybubbling nitrogen gas into the solution for 0.5 h followed by additionof PdCl₂(dppf) (0.54 g, 0.74 mmol) and Pd₂(dba)₃ (0.34 g, 0.37 mmol).The resulting reaction mixture was stirred at 90° C. for 8 h. Thereaction was then poured into ice-cold water (500 mL). The aqueous layerwas extracted with ethyl acetate (100 mL×3). The combined organic layerswere dried over anhydrous Na₂SO₄ and concentrated under vacuum. Thecrude product was purified by chromatography on SiO₂ (eluting with 15%ethyl acetate in hexane) to afford the title compound (4.5 g, 55%).

¹H-NMR (400 MHz, DMSO-d₆) δ 9.72 (s, 1H), 8.49 (dd, J=4.4, 1.2 Hz, 1H),7.97 (dd, J=8.4, 1.2 Hz, 1H), 7.70 (dd, J=8.4, 4.4 Hz, 1H), 1.49 (s,9H).

Step 3: tert-butyl (2-(aminomethyl)pyridin-3-yl)carbamate

To a stirred solution of 1-(tert-butyl (2-cyanopyridin-3-yl) carbamate(3.80 g, 17.30 mmol) in ethyl acetate (100 mL) was added Raney nickel(0.76 mL, 20%). The reaction was stirred at room temperature for 6 hunder hydrogen (40 bar). The mixture was then filtered through a Celitepad and the filtrate was concentrated under vacuum to afford the titlecompound (4.3 g).MS (ESI-MS): m/z calcd for C₁₁H₁₇N₃O₂ [MH]+223.13, found 224.52 [M+1].

Step 4: tert-butyl (2-(formamidomethyl)pyridin-3-yl)carbamate

Tert-butyl (2-(aminomethyl) pyridin-3-yl) carbamate (4.30 g, 19.20 mmol)in ethyl formate (100 mL) was heated at 65° C. for 16 h. The reactionmixture was cooled to room temperature and concentrated under vacuum.The crude product was purified by chromatography on SiO₂ (eluting with2.5% MeOH in DCM) to afford the title compound (2.80 g, 11.14 mmol).

¹H-NMR (400 MHz, DMSO-d₆) δ 9.13 (s, 1H), 8.65 (s, 1H), 8.29 (dd, J=4.8,1.6 Hz, 1H), 8.10 (d, J=1.6 Hz, 1H), 7.87 (dd, J=7.6 Hz, 1H), 7.31 (q,J=8.0 Hz, 4.4 Hz, 1H), 4.38 (d, J=6.0 Hz, 2H), 1.47 (s, 9H).

Step 5: tert-butyl imidazo[1,5-a]pyridin-8-ylcarbamate

To a stirred solution of tert-butyl (2-(formamidomethyl) pyridin-3-yl)carbamate (2.80 g, 11.10 mmol) in DCM (50 mL) was added TEA (4.7 mL,33.3 mmol) at room temperature. POCl₃ was then added drop wise at 0° C.The resulting reaction mixture was allowed to stir at 0° C. for 1 hbefore being poured into NaHCO₃ (sat., 50 mL). The aqueous layer wasextracted with dichloromethane (250 mL×2). The combined organic layerswere dried over anhydrous Na₂SO₄ and concentrated under vacuum to affordthe title compound (3.5 g, 57%).

Step 6: imidazo[1,5-a]pyridin-8-amine hydrochloride

To a stirred solution of tert-butyl imidazo [1,5-a]pyridin-8-ylcarbamate (3.50 g, 15.00 mmol) in DCM (30 mL) was added HCl(4M in dioxane, 35 mL) at room temperature. The resulting reactionmixture was allowed to stir at room temperature for 2 h. The solutionwas then concentrated under vacuum to afford the title compound (4.00g).

¹H-NMR (400 MHz, DMSO-d₆) δ 10.65 (s, 1H), 9.58 (s, 1H), 8.25 (s, 1H),7.88 (d, J=6.8 Hz, 1H), 6.92 (t, J=7.2 Hz, 1H), 6.11 (d, J=7.6 Hz, 1H).

Step 7: 8-azidoimidazo [1,5-a] pyridine

To a stirred solution of imidazo[1,5-a]pyridin-8-amine hydrochloride(0.50 g, 3.70 mmol) in acetonitrile (10 mL) was added t-butyl nitrite(1.2 g, 11.2 mmol) at 0° C. and stirring was continued for 5 min at 0°C. A solution of NaN₃ (0.96 g, 14.8 mmol) in water (0.5 mL) was added at0° C. The reaction was then stirred at 0° C. for 1 h. The reaction wasrepeated in the same manner, combined and was poured into water (10 mL).The aqueous layer was extracted with ethyl acetate (30 mL×2). Thecombined organic layers were dried over Na₂SO₄ and concentrated undervacuum to afford the title compound (0.05 g, 10%).

¹H-NMR (400 MHz, DMSO-d₆) δ 8.46 (s, 1H), 8.21-8.19 (m, 1H), 7.38 (s,1H), 6.71-6.65 (m, 2H).

Intermediate 29: 4-azidoisoquinoline

To a stirred solution of isoquinolin-4-amine (1.00 g, 6.90 mmol) inacetic acid (10 mL) was added NaNO₂ (0.96 g, 13.80 mmol) in water (3mL). The addition was drop-wise at 0° C. after which the reaction wasstirred for a further 15 minutes at 0° C. An additional aliquot of NaN₃(0.90 g, 13.80 mmol) in water (3 mL) was added drop-wise at 0° C. Thereaction was then stirred at room temperature for 2 h. before beingpoured into water (30 mL). The aqueous layer was extracted with ethylacetate (30 mL×3). The organic layers were dried over Na₂SO₄ andconcentrated under vacuum. The crude product was purified bychromatography on SiO₂ (eluting with 20% ethyl acetate in hexane) toafford the title compound (0.35 g, 30%).

¹H-NMR (400 MHz, DMSO-d₆) δ 9.16 (s, 1H), 8.56 (s, 1H), 8.17 (d, J=8.0Hz, 1H), 8.01 (d, J=8.0 Hz, 1H), 7.85 (td, J=6.8, 1.2 Hz, 1H), 7.77 (td,J=8.0, 0.8 Hz, 1H).

Example 141:(cyclobutylmethyl)[(6-{[1-(1H-indazol-4-yl)-1H-1,2,3-triazol-4-yl]methyl}-1H-indol-2-yl)methyl]amine

Step 1: tert-butyl2-({[(tert-butoxy)carbonyl](cyclobutylmethyl)amino}methyl)-6-({1-[1-(oxan-2-yl)-1H-indazol-4-yl]-1H-1,2,3-triazol-4-yl}methyl)-1H-indole-1-carboxylate

A mixture of tert-butyl2-(((tert-butoxycarbonyl)(cyclobutylmethyl)amino)methyl)-6-(prop-2-yn-1-yl)-1H-indole-1-carboxylateIntermediate 26 (0.200 g, 0.440 mmol), 4-azido-1-(oxan-2-yl)-1H-indazoleIntermediate 25 (0.107 g, 0.440 mmol), sodium ascorbate (0.035 g, 0.176mmol) and CuSO₄ (0.028 g, 0.176 mmol) in tert-butanol:water (1:1, 2 mL)was heated at 70° C. for 1 h. The reaction was cooled to roomtemperature and poured into water (150 mL). The aqueous layer wasextracted with ethyl acetate (50 mL×3). The combined organic layers weredried over Na₂SO₄ and concentrated under vacuum. The crude product waspurified by chromatography on SiO₂ (eluting with (34% ethyl acetate inhexane) to afford the title compound (0.150 g, 48%).Method G: LC-MS (electrospray): m/z=696.8 (M+H)⁺, RT=3.38 min

Step 2:(cyclobutylmethyl)[(6-{[1-(1H-indazol-4-yl)-1H-1,2,3-triazol-4-yl]methyl}-1H-indol-2-yl)methyl]amine

To a stirred solution of2-(((tert-butoxycarbonyl)(cyclobutylmethyl)amino)methyl)-6-((1-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-1H-1,2,3-triazol-4-yl)methyl)-1H-indole-1-carboxylate(0.150 g, 0.21 mmol) in 1,4-dioxane (1.5 mL) was added HCl (4M indioxane, 5.00 mL) drop-wise at room temperature. The resulting mixturewas allowed to stir at room temperature for 16 h. The mixture was pouredinto Na₂CO₃ solution (sat., 100 mL) and extracted with ethyl acetate(3×30 mL). The combined organic layers were dried over Na₂SO₄ andconcentrated under vacuum. The crude product was purified bychromatography on SiO₂ eluting with (6% MeOH in dichloromethane) toafford the title compound (0.015 g, 16%).Method G: LC-MS (electrospray): m/z=412 (M+H)⁺, RT=1.34 min

¹H NMR: (MeOD, 400 MHz) δ 8.46 (d, J=4.4 Hz, 2H), 7.67 (d, J=8.0 Hz,1H), 7.56-7.49 (m, 3H), 7.40 (s, 1H), 7.11 (d, J=8.0 Hz, 1H), 6.61 (s,1H), 4.31 (d, J=8.8 Hz, 4H), 3.08 (d, J=7.6 Hz, 2H), 2.72-2.66 (m, 1H),2.21-2.14 (m, 2H), 2.04-1.81 (m, 4H)

The compounds in Table 5 were prepared from the appropriateintermediates in a similar manner to Example 141.

TABLE 5 LCMS Compound LCMS Retention No Name Structure method time MassIon 142 [(3,3- difluorocyclobutyl) methyl] [(6-{[1-(1H- indazol-4-yl)-1H-1,2,3- triazol-4- yl]methyl}- 1H-indol-2- yl)methyl] amine

G 1.36 448.2 143 (cyclobutylmethyl) [(6-{[1- (isoquinolin- 4-yl)-1H-1,2,3-triazol- 4-yl]methyl}- 1H-indol-2- yl)methyl] amine

C 3.53 423.4 144 (cyclobutylmethyl) ({6-[(1- {imidazo[1,5- a]pyridin-8-yl}-1H-1,2,3- triazol-4- yl)methyl]- 1H-indol-2- yl}methyl) amine

C 3.17 412.4

Intermediate 30: 3-ethynyl-5-methoxypyridine-2-carbonitrile

The title compound was prepared from3-bromo-5-methoxy-pyridine-2-carbonitrile (Example 63 Step 1) usingprocedures similar to those described in Example 63 Steps 5 and 6 toprovide the title compound (564 mg, 97%) as a beige solid.Method A: LC-MS (electrospray): m/z=159.0 (M+H)⁺, RT=0.98 min

Intermediate 33: 3-ethynyl-5-fluoropyridine-2-carbonitrile

The title compound was prepared from3-bromo-5-fluoropyridine-2-carbonitrile using procedures similar tothose described in Example 63 Steps 5 and 6 to provide the titlecompound (306 mg, 97%) as a pale brown solid. 1H NMR (400 MHz, CDCl3) δ8.54 (d, J=2.7 Hz, 1H), 7.62 (dd, J=7.9, 2.7 Hz, 1H), 3.70 (s, 1H).

Intermediate 34: 3-ethynyl-5-methoxypyridine

The title compound was prepared from 3-bromo-5-methoxypyridine usingprocedures similar to those described in Example 63 Steps 5 and 6 toprovide the title compound (306 mg, 97%) as a brown solid.Method A: LC-MS (electrospray): m/z=134.0 (M+H)⁺, RT=0.86 min

Intermediate 31: 6-(azidomethyl)-1H-indole-2-carbaldehyde

Step 1: 6-bromo-2-(dimethoxymethyl)-1H-indole

A suspension of 6-bromo-1H-indole-2-carbaldehyde (500 mg, 2.23 mmol) andtrimethoxymethane (3.9 mL, 35.7 mmol) in methanol (1.5 mL) was treatedwith 4-methylbenzenesulfonic acid hydrate (4.2 mg, 0.02 mmol) and themixture was stirred at room temperature for 30 minutes which resulted information of a black solution.The mixture was diluted with NaHCO₃ (sat., 5 mL) and extracted with DCM(3×10 mL). The combined organics were washed with brine (10 mL), driedover magnesium sulfate and concentrated to give a brown oil which waspurified by chromatography on SiO₂ (eluting with 0-100% EtOAc inheptane) to afford the title compound (570 mg, 91%) as an orange oil.Method J: LC-MS (electrospray): m/z=268.2/270.2 (M+H)⁺, RT=0.81 min

Step 2: 2-(dimethoxymethyl)-1H-indole-6-carbaldehyde

Sodium hydride (60%, 397 mg, 9.92 mmol) was added to an ice-cooledsolution of 6-bromo-2-(dimethoxymethyl)-1H-indole (670 mg, 2.48 mmol) inTHF-Anhydrous (20 mL) and the mixture was stirred under ice-cooling for10 minutes. The mixture was cooled to −78° C. and 2.5 M n-BuLi inhexanes (5.0 mL, 12.4 mmol) was added. The reaction mixture was stirredand allowed to warm slowly to −10° C. over 3 hours.

Anhydrous DMF (1.2 mL, 14.9 mmol) was added at −10° C. and the reactionmixture was stirred and allowed to warm to 0° C. over 30 minutes.The mixture was then quenched with NH₄Cl (sat., 30 mL) and extractedwith EtOAc (3×30 mL). The combined organic layers were washed with brine(2×40 mL), dried (MgSO₄) and concentrated under reduced pressure. Thecrude material was purified by chromatography on SiO₂ (eluting with0-100% EtOAc in heptane) to afford the title compound (440 mg, 78%) asan off-white solid.Method J: LC-MS (electrospray): m/z=220.2 (M+H)⁺, RT=0.62 min

Step 3: 6-(azidomethyl)-1H-indole-2-carbaldehyde

The title compound was prepared from2-(dimethoxymethyl)-1H-indole-6-carbaldehyde using procedures similar tothose described in Example 140 Steps 4-7 to provide (155 mg, 70%) as anoff-white solid.Method J: LC-MS (electrospray): m/z=199.4 (M+H)⁺, RT=0.66 min

Intermediate 32:3-[1-[(2-formyl-1H-indol-6-yl)methyl]triazol-4-yl]-5-methoxy-pyridine-2-carbonitrile

The title compound was prepared from Intermediate 31 and intermediate 30using the procedure described in Example 14 step 9 to give (588 mg, 78%)as a pale brown solid.Method A: LC-MS (electrospray): m/z=359.0 (M+H)⁺, RT=1.07 min

Example 146:3-[1-({2-[(4,4-Dimethyl-1-piperidyl)methyl]-1H-indol-6-yl}methyl)-1H-1,2,3-triazol-4-yl]-5-methoxy-2-pyridinecarbonitrile

3-[1-[(2-formyl-1H-indol-6-yl)methyl]triazol-4-yl]-5-methoxy-pyridine-2-carbonitrile(Intermediate 32) (100 mg, 0.15 mmol), 4,4-dimethylpiperidinehydrochloride (65 mg, 0.44 mmol) and triethylamine (81 μl, 0.58 mmol)were combined in DCE (3 ml) and the mixture was heated at 70° C. for 10minutes before sodium triacetoxyborohydride (154 mg, 0.73 mmol) wasadded—slight gas evolution—and the mixture was heated at 70° C. for 3hours.The mixture was cooled to room temperature, quenched with NaHCO₃(Aq)(sat., 20 ml) and extracted with chloroform/isopropanol (3:1, 3×30 ml)and the combined organic extracts were dried over sodium sulfate andevaporated under vacuum.

The residue was purified by reverse phase chromatography (30 g Sfar C18,eluting with acetonitrile+0.1% NH3/Water+0.1% NH3 10-100%) to afford thetitle compound (34 mg, 51%) as an off-white solid.

Method C: LC-MS (electrospray): m/z=456.4 (M+H)⁺, RT=4.14 min

TABLE 6 The compounds in Table 6 were prepared in the same fashion asExample XXX using the appropriate amine. LCMS Compound LCMS RetentionMass No Name Structure method time Ion 147 3-{(1-[(2-{(6- Aza-6-spiro[3.4]octyl) methyl}- 1H-indol-6- yl)methyl]- 1H-1.2.3-triazol-4-yl}- 5-methoxy- 2- pyridinecarbonitrile

C 4.03 454.4 148 3-[1-(2- [({(Bicyclo[1.1.1] pent-1- yl)methyl}amino)methyl]- 1H-indol-6- yl}methyl)- 1H-1,2,3- triazol-4-yl]-5-methoxy- 2- pyridinecarbonitrile

C 3.70 440.4 149 3-[1-({2- [({(3- Fluorobicyclo [1.1.1]pent-1-yl)methyl} amino)methyl]- 1H-indol-6- yl}methyl)- 1H-1,2,3-triazol-4-yl]- 5-methoxy-2- pyridinecarbonitrile

C 3.45 458.5 150 5-Methoxy- 3-[1-({2-[({(3- methylbicyclo [1.1.1]pent-1-yl)methyl} amino)methyl]- 1H-indol-6- yl}methyl)- 1H-1,2,3-triazol-4-yl]- 2- pyridinecarbonitrile

C 3.90 454.6

Example 151:3-{1-[(2-{[(Cyclobutylmethyl)amino]methyl}-1H-indol-6-yl)methyl]-1H-1,2,3-triazol-4-yl}-5-methoxy-2-pyridinecarbonitrile

The title compound was prepared from Intermediate 7 and Intermediate 30using the procedures described in Example 141 to give (146 mg, 67%) as awhite solid.Method C: LC-MS (electrospray): m/z=428.5 (M+H)⁺, RT=3.54 min

Example 152:3-(1-((2-(((cyclobutylmethyl)amino)methyl)-1H-indol-6-yl)methyl)-1H-1,2,3-triazol-4-yl)-5-fluoropicolinonitrile

The title compound was prepared from Intermediate 7 and Intermediate 33using the procedures described in Example 141 to give (97 mg, 46%) as awhite solid.Method C: LC-MS (electrospray): m/z=416.4 (M+H)⁺, RT=3.71 min

Example 153:1-cyclobutyl-N-((6-((4-(5-methoxypyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)-1H-indol-2-yl)methyl)methanamine

The title compound was prepared from Intermediate 7 and Intermediate 34using the procedures described in Example 141 to give (50 mg, 33%) as anoff-white solid.Method C: LC-MS (electrospray): m/z=403.4 (M+H)⁺, RT=3.27 min

Example 154:5-chloro-3-(1-((2-(((cyclobutylmethyl)amino)methyl)-1H-indol-6-yl)methyl)-1H-1,2,3-triazol-4-yl)picolinonitrile

Step 1: tert-butyl2-[[tert-butoxycarbonyl(cyclobutylmethyl)amino]methyl]-6-[[4-(6-methyl-4,8-dioxo-1,3,6,2-dioxazaborocan-2-yl)triazol-1-yl]methyl]indole-1-carboxylate

A mixture of ethynylboronic acid MIDA ester (77 mg, 0.426 mmol),tert-butyl6-(azidomethyl)-2-[[tert-butoxycarbonyl(cyclobutylmethyl)amino]methyl]indole-1-carboxylateIntermediate 7 (200 mg, 0.426 mmol) and Cu(OAc)₂.H₂O (8.5 mg, 0.04 mmol)was diluted with acetonitrile (4 mL) and heated at 60° C. for 18 hours.The blue suspension was evaporated under vacuum (blast shield) and theresidue was purified by chromatography on SiO₂ (eluting with 40-100%EtOAc in heptane followed by 10% MeOH in EtOAc) to give the titlecompound (204 mg, 53%) as a white foam.Method J: LC-MS (electrospray): m/z=651.6 (M+H)⁺, RT=0.99 min

Step 2: tert-butyl2-[[tert-butoxycarbonyl(cyclobutylmethyl)amino]methyl]-6-[[4-(5-chloro-2-cyano-3-pyridyl)triazol-1-yl]methyl]indole-1-carboxylate

A microwave vial containing tert-butyl2-[[tert-butoxycarbonyl(cyclobutylmethyl)amino]methyl]-6-[[4-(6-methyl-4,8-dioxo-1,3,6,2-dioxazaborocan-2-yl)triazol-1-yl]methyl]indole-1-carboxylate(100 mg, 0.111 mmol), 3-bromo-5-chloropyridine-2-carbonitrile (30 mg,0.138 mmol), K₂CO₃ (107 mg, 0.78 mmol), Cu(OAc)₂.H₂O (11 mg, 0.0553mmol) and Palladium-Xphos G2 (4.4 mg, 5.53 μmol) was sealed, dilutedwith MeCN (2 mL) and IPA (0.5 mL) and heated under microwave irradiationat 120° C. for 2×20 minutes.The mixture diluted with DCM and a little water to dissolve the fewsolids and concentrated under vacuum. The residue was diluted with waterand extracted with DCM. The extracts were evaporated under vacuum to abrown gum which was purified by chromatography on SiO₂ (eluting withEtOAc) to give the desired product (contaminated with ˜20% ofde-chlorinated side product) (33 mg, 47%) as a clear gum.Method J: LC-MS (electrospray): m/z=632.6 (M+H)⁺, RT=1.19 min

Step 3:5-chloro-3-(1-((2-(((cyclobutylmethyl)amino)methyl)-1H-indol-6-yl)methyl)-1H-1,2,3-triazol-4-yl)picolinonitrile

A solution of tert-butyl2-[[tert-butoxycarbonyl(cyclobutylmethyl)amino]methyl]-6-[[4-(5-chloro-2-cyano-3-pyridyl)triazol-1-yl]methyl]indole-1-carboxylate(33 mg, 0.05 mmol) in MeOH (0.3108 mL) was treated with HCl (4M indioxane, 0.6 mL), and the resulting mixture was stirred at roomtemperature for one hour. Further HCl (4M in dioxane, 0.6 mL) was addedand the mixture was stirred at room temperature for 36 hours.The reaction mixture was retreated with HCl (4M in dioxane, 0.6 mL), andthe mixture left to stir at room temperature for 18 hours.The pink mixture was evaporated under vacuum and the residue waspurified by preparative HPLC (method B), and the product containingfractions were combined, concentrated in vacuo and freeze dried to givethe title compound (8.6 mg, 38% Yield) as a white solid.Method C: LC-MS (electrospray): m/z=432.5 (M+H)⁺, RT=3.78 min

Example 155:2-((6-azaspiro[3.4]octan-6-yl)methyl)-6-((4-(imidazo[1,5-a]pyridin-8-yl)-1H-1,2,3-triazol-1-yl)methyl)-1H-pyrrolo[3,2-c]pyridine

The title compound was prepared from 6-azaspiro[3.4]octane in a similarmanner to Example 140 to give the title compound (24 mg, 40%) as a beigesolid.Method C: LC-MS (electrospray): m/z=439.4 (M+H)⁺, RT=2.95 min

METTL3/14 Methyltransferase Assay Biochemical Assay

The enzymatic assay was established to determine IC50 values forinhibition of RNA methyltransferase activity. The enzyme used wasfull-length his-tagged METTL3 co-expressed with full length FLAG-taggedMETTL14 in a baculovirus expression system. Enzymatic reactions wereperformed at room temperature in 384-well plates using a final reactionvolume of 20 μL containing 20 mM TrisCl pH 7.6, 1 mM DTT, 0.01%Tween-20. 5 nM final concentration of METTL3/14 was pre-incubated withvarious compound concentrations for 10 minutes, followed by addition of0.2 μM final concentration synthetic RNA substrate(5′P-uacacucgaucuggacuaaagcugcuc-3′) and 0.5 μM final concentrationS-adenosyl-methionine (SAM). The reaction was incubated for further 60minutes at room temperature, and then quenched by the addition of 40 μL7.5% TCA with two internal product standards (D₄-SAH and ¹³C₁₀-SAH).After termination, plates were sealed, centrifuged and stored at 4° C.until analysis.

Mass Spectrometry Analysis

RNA methyltransferase activity was measured label free using theRapidFire™ mass spectrometry (RF/MS) platform. Stopped and stable assayplates were analyzed on the Agilent RF300 integratedautosampler/solid-phase extraction (SPE) system coupled to an ABSciex4000 mass spectrometer for the generation of the product S-adenosylhomocysteine (SAH) and normalized to the ratio of signal of the twointernal product standards, respectively. Solvent A was water containing0.1% (v/v) TCA. Solvent B was acetonitrile/0.1% ammonium acetate (8:2,v/v). More specifically, plates were centrifuged at 4350 rpm for 10 min,samples were aspirated under vacuum for 600 ms, then loaded onto a C18solid-phase extraction cartridge and washed for 3 s with solvent A at aflow rate of 1.5 mL/min. Retained product and internal standards wereeluted with solvent B at a flow rate of 1 mL/min for 3 s and finally thecartridge was reequilibrated with solvent A for 500 ms. The masstransition for the product (SAH) was 384.9/135.9 Da. Transitions of thetwo internal product standards (IS1: D₄-SAH and IS2: ¹³C₁₀-SAH) were389.1/135.8 Da and 395.0/134.2 Da, respectively. Ratios of SAH/IS1 andSAH/IS2 were used for normalization of matrix effects. IC50 values werecalculated based on dilution series of individual compounds. Potency ofa compound was measured at varied inhibitor concentrations andnormalized to control wells without RNA substrate and without inhibition(DMSO only).

Results:

TABLE 6 Example No METTL3_14 IC50 nM 1 3.84 2 6.1 3 6.1 4 6.1 5 17.6 66.1 7 88.6 8 9.53 9 228 10 603 11 6.1 12 26.8 13 14 14 15.1 15 6.1 1615.6 17 70.8 18 19.2 20 66.4 21 6.62 22 6.28 23 6.1 24 11.7 25 11.7 266.1 27 6.1 28 9.32 29 8.64 30 6.1 31 10.7 32 636 33 8.11 34 6.1 35 6.136 6.1 37 10.7 38 6.1 39 10.2 40 12.29 41 6.1 42 1220 43 1160 44 756 456.1 46 5080 47 6.1 48 12.5 49 6.86 50 1090 51 6680 52 5080 53 22.1 547.83 55 6.1 56 11.6 57 6.1 58 6.1 59 6.1 60 6.1 61 10.6 62 6.1 63 8.1464 6.82 65 16100 66 15.9 67 6.1 68 9.86 69 17.2 70 11.3 71 192 72 32.173 199 74 260 75 35.2 76 6.1 77 6.1 78 75.3 79 488 80 445 81 6.1 82 37483 9.32 84 150 85 67.8 86 158 87 309 88 106 89 113 90 6.1 123 118 1226.1 121 80.9 91 638 92 6.1 93 6.1 94 6.1 95 6.1 96 9.24 97 7.2 98 14.899 6.66 100 6.99 124 6.1 101 193 102 6.1 115 564 103 185 114 6.1 104 6.1116 6.1 105 71.6 106 6.1 120 6.1 117 6.1 118 9.22 119 8.97 107 13.5 10817.8 125 6.1 113 6.1 112 125 111 7.54 110 6.1 109 6.1 129 6.1 130 6.1131 6.1 132 6.1 126 6.1 127 6.1 133 11.4 134 6.1 135 6.3 136 18.8 1376.1 138 6.1 139 24.4 140 6.53 141 7.02 142 7.91 143 495 144 19.3 145<6.1 146 26.8 147 26.4 148 <6.1 149 6.91 151 34.6 152 259 153 6.8 15471.04 155 <6.1Note: in Table 6, IC50=6.1 nM represents the bottom limit of the assay.

Kasumi Cell Assay

Cell culture: KASUMI-1 cells (ACC20, Leibniz-Institut DSMZ DeutscheSammlung von Mikroorganismen und Zellkulturen GmbH) were grown in RPMI1640 (31870-025, Gibco) supplemented with 20% fetal bovine serum (F1524,Gibco), 1 mM sodium pyruvate (11360-039, Gibco) and 2 mM Glutamax(35050-038, Gibco) in a 5% CO2 humidified incubator at 37° C.Cell treatment and cell growth assessment: KASUMI-1 hours were seeded inultra-low attachment 384-well culture plate (MS-9384WZ, SBio) at a finalconcentration of 250 000 cells/ml (35 μL/well) and treated for 120 hourswith compounds inhibiting the METTL3/14 activity (10 serial semi-logdilutions, 30 μM as top concentration). Upon treatment, Kasumi1 cellswere incubated for 10 min at RT with the CellTiter-Glo reagent (G7571,Promega). Measurement of the luminescence signal was performed on amicroplate reader (Ensight, PerkinElmer).

TABLE 7 Results: Example No KASUMI1 cells IC50 nM 2 586.7 23 262.9 382306 41 309 45 764 47 343.8 60 2177 63 868.9 67 1723 70 4895 76 698 771765 81 1030 83 3679 90 1247 92 1610 93 1330 94 2237 95 3188 97 3094 993256 100 2544 102 524.7 104 661.1 106 1828 109 1474 110 1145 111 2287113 1653 114 1458 116 5072 117 1726 120 446.9 122 1105 124 662.1 125 504126 3069 129 2903 130 3155 131 1140 132 784.9 140 1086 145 717.2 1517215 152 9963 155 546.7

CTG Assay (Caov3 Cell Line)

Cell culture: Caov-3 cells (HTB-75, Lot number: 70016791, ATCC) weregrown in DMEM (11960-04431053-028, Gibco) supplemented with 10% fetalbovine serum (1600-44, Gibco), 1 mM sodium pyruvate (11360-039, Gibco)and 2 mM Glutamax (35050-038, Gibco) at 37° C. with 5% CO2.Cell treatment and cell growth assessment: 18 hours post-seeding inwhite 384-Viewplate (6007480, PerkinElmer) at 1500 cells/well, Caov3cells were treated for 120 hours with compounds inhibiting the METTL3/14activity (10 serial semi-log dilutions, 30 μM as top concentration).Upon treatment, Coav-3 cells were incubated for 10 min at RT with theCellTiter-Glo reagent (G7571, Promega). Measurement of the luminescencesignal was performed on a microplate reader (Ensight, PerkinElmer).

Caov3 CTG Assay—Proliferation Assay

TABLE 8 Example No Caov3 cells IC50 nM 1 260 2 237.1 6 756.5 11 606.8 15657.6 21 745.6 23 80.1 25 732.4 26 274 27 419.7 31 933 34 988 35 118 36973.1 38 458.1 40 1030 41 191.7 45 574.2 47 185.5 49 1056 54 837.4 55763.8 57 1060 58 702 59 523.9 60 422.9 62 695.5 63 256.8 64 922.5 67481.8 76 241.9 77 700.7 81 564 90 601.5 92 597.5 93 452.6 94 681 95959.6 97 1025 99 1090 100 685.4 102 229.7 104 237.3 106 911 109 608.4110 411.5 113 574.6 114 679 117 502.4 120 203.4 122 524.6 124 266.2 125212.3 126 522.8 127 623.6 128 1056 129 699.3 130 457.3 131 237.3 132 268135 268.7 137 1080 140 296.9 145 201.2 151 9055 152 5431 155 472.9

Numbered Paragraphs

The following numbered paragraphs are not claims, but serve to defineparticular aspects and embodiments of the invention:1. A compound of formula (I) shown below, or a pharmaceuticallyacceptable salt thereof:

X—Y—Z  (I)

wherein:X is selected from:

whereinQ₁ is selected from NH, N—C₁₋₄alkyl, O or S;Q_(2a) is selected from N or CR₂a;Q_(2b) is selected from N or CR_(2b);Q_(2c) is selected from N or CR₂c;Q_(2d) is selected from N or CR_(2d);Q₃ is selected from N or CR_(1b);Q₄ is selected from N or CR_(1x);subject to the proviso that no more than 3 of Q₁, Q_(2a), Q_(2b),Q_(2c), Q_(2d), Q₃ and Q₄ are nitrogen;R_(1a) is selected from:

-   -   (i) C₁₋₄alkyl or C₁₋₄alkoxy, each of which being optionally        substituted by halo, cyano, hydroxy, C₃₋₆cycloalkyl, C₁₋₄alkoxy,        C₁₋₄haloalkoxy, aryl or heteroaryl; or    -   (ii) a group of the formula:

—(CR_(1c)R_(1d))_(p)—NR_(1e)R_(1f);

-   -   wherein        -   p is an integer selected from 0, 1, 2 or 3        -   R_(1c) and R_(1d) are independently selected from:            -   (i) hydrogen (including deuterium),                -   (ii) C₁₋₆alkyl which is optionally substituted by                    one more substituents selected from cyano, oxo,                    hydroxy, C₁₋₄alkoxy, halo, C₁₋₄haloalkoxy,                    C₃₋₆cycloalkyl, —O—C₃₋₆cycloalkyl, NR_(1ca)R_(1da)                    or —S(O)₀₋₂R_(1ca)R_(1da), wherein R_(1ca) and                    R_(1da) are H or C₁₋₂alkyl; and wherein                    C₃₋₆cycloalkyl and —O—C₃₋₆cycloalkyl are optionally                    further substituted with halo, cyano or hydroxy;                -   (iii) C₃₋₄cycloalkyl or 3 to 5 membered                    heterocyclyl, each of which is optionally                    substituted by C₁₋₄alkyl, C₁₋₄haloalkyl, cyano,                    hydroxy, C₁₋₂alkoxy, halo, C₁₋₂haloalkoxy,                    NR_(1ca)R_(1da) or —S(O)₀₋₂R_(1ca)R_(1da), wherein                    R_(1ca) and R_(1da) are H or C₁₋₂alkyl; and;                -   (iv) or R_(1c) and R_(1d) are linked together such                    that, together with the carbon atom to which they                    are attached, they form a 3- to 6-membered                    cycloalkyl or heterocyclic ring, or a spirocyclic                    ring system, each of which is optionally substituted                    by one or more substituents selected from C₁₋₂alkyl,                    C₁₋₂haloalkyl, cyano, hydroxy, C₁₋₂alkoxy, halo,                    C₁₋₂haloalkoxy, NR_(1ca)R_(1da) or                    —S(O)₀₋₂R_(1ca)R_(1da), wherein R_(1ca) and R_(1da)                    are H or C₁₋₂alkyl;    -   R_(1e) and R_(1f) are each independently selected from:        -   (i) hydrogen (including deuterium);            -   (ii) C₁₋₆alkyl which is optionally substituted by one                more substituents selected from cyano, hydroxy,                C₁₋₂alkoxy, halo, C₁₋₂haloalkoxy, NR_(1ea)R_(1fa) or                —S(O)₀₋₂R_(1ea)R_(1fa), wherein R_(1ea) and R_(1fa) are                H or C₁₋₂alkyl;            -   (iii) a group with the formula:

—(CR_(1g)R_(1h))_(q)-T₁

-   -   -   -   -   wherein:                -   q is 0, 1, 2, 3, 4, 5 or 6;                -   R_(1g) and R_(1h) are independently selected from:                -    e) hydrogen;                -    f) C₁₋₆alkyl which is optionally substituted by one                    more substituents selected from cyano, oxo, hydroxy,                    C₁₋₄alkoxy, halo, C₁₋₄haloalkoxy, —O—C₃₋₆cycloalkyl,                    NR_(1ga)R_(1ha) or —S(O)₀₋₂R_(1ga)R_(1ha), wherein                    R_(1ga) and R_(1ha) are H or C₁₋₂alkyl; and wherein                    —O—C₃₋₆cycloalkyl is optionally substituted with                    halo, cyano or hydroxy;                -    g) an aryl-C₁₋₆alkyl, heteroarylC₁₋₆alkyl,                    C₃₋₆-cycloalkyl or C₃₋₆cycloalkylC₁₋₆alkyl group,                    each of which is optionally substituted by one or                    more substituents selected from C₁₋₂alkyl, cyano,                    C₁₋₂haloalkyl, hydroxy, C₁₋₂alkoxy, halo,                    C₁₋₂-haloalkoxy, NR_(1ga)R_(1ha) or                    —S(O)₀₋₂R_(1ga)R_(1ha), wherein R_(1ga) and R_(1ha)                    are H or C₁₋₂alkyl; or                -    h) or R_(1g) and R_(1h) are optionally linked                    together such that, together with the carbon atom to                    which they are attached, they form a 3- to                    6-membered cycloalkyl or heterocyclic ring which is                    optionally substituted by one or more substituents                    selected from C₁₋₂alkyl, cyano, C₁₋₂haloalkyl,                    hydroxy, C₁₋₂ alkoxy, halo, C₁₋₂haloalkoxy,                    NR_(1ga)R_(1ha) or —S(O)₀₋₂R_(1ga)R_(1ha), wherein                    R_(1ga) and R_(1ha) are H or C₁₋₂alkyl;

            -   and T₁ is selected from hydrogen, cyano, hydroxy,                NR_(1t)R_(2t) or —S(O)₀₋₂R_(1t)R_(2t) (wherein R_(1t)                and R_(2t) are H or C₁₋₄alkyl), C₃₋₆cycloalkyl,                C₂₋₃alkenyl, C₂₋₃alkynyl, aryl, heterocyclyl,                heteroaryl, a spirocyclic carbocyclic or heterocyclic                ring system, a bridged C₃₋₈cycloalkyl, a bridged                bicyclic C₅₋₁₂cycloalkyl, or a bridged heterocyclic ring                system, each of which is optionally substituted by one                or more substituents selected from C₁₋₂alkyl,                C₁₋₂-haloalkyl, cyano, hydroxy, C₁₋₂alkoxy, halo,                C₁₋₂-haloalkoxy, NR_(3t)R_(4t) or —S(O)₀₋₂R_(3t)R_(4t),                wherein R_(3t) and R_(4t) are H or C₁₋₂alkyl;

        -   (iv) or R_(1e) and R_(1f) are linked such that, together            with the nitrogen atom to which they are attached, they form            a mono- or bicyclic-heterocyclic ring, which is optionally            substituted by one or more substituents selected from            C₁₋₄alkyl, C₁₋₄haloalkyl, cyano, hydroxy, C₁₋₄alkoxy, halo,            C₁₋₄haloalkoxy, NR_(1i)R_(1j) or —S(O)₀₋₂R_(1i)R_(1j),            wherein R_(1i) and R_(1j) are H or C₁₋₄alkyl, and/or the            mono- or bicyclic hetereocyclic ring formed by R_(1e) and            R_(1f) is optionally spiro-fused to a C₃₋₆cycloalkyl or a            heterocyclic ring, which in turn is optionally substituted            by one or more substituents selected from C₁₋₄alkyl,            C₁₋₄haloalkyl, cyano, hydroxy, C₁₋₄ alkoxy, halo,            C₁₋₄haloalkoxy, NR_(1i)R_(1j) or —S(O)₀₋₂R_(1i)R_(1j),            wherein R_(1i) and R_(1j) are H or C₁₋₄alkyl;            R_(1b) is selected from hydrogen, cyano, halo or C₁₋₃ alkyl;            R_(1x) is selected from hydrogen, cyano, halo or C₁₋₃ alkyl;            R_(2a), R_(2b), R_(2c) and R_(2d) are independently selected            from hydrogen, cyano, halo or a group of the formula:

-L_(2a)-L_(2b)-Q₂

wherein

-   -   L_(2a) is absent or C₁₋₃alkylene optionally substituted by C₁₋₂        alkyl or oxo;    -   L_(2b) is absent or selected from O, S, SO, SO₂, N(R_(n)), C(O),        C(O)O, OC(O), C(O)N(R_(n)), N(R_(n))C(O), N(R_(n))C(O)N(R_(o)),        S(O)₂N(R_(n)), or N(R_(n))SO₂, wherein R_(n) and R_(o) are each        independently selected from hydrogen or C₁₋₂alkyl; and    -   Q₂ is hydrogen, cyano, C₁₋₆alkyl, C₃₋₆cycloalkyl, aryl,        heterocyclyl or heteroaryl, each of which is optionally        substituted by one or more substituents selected from halo,        trifluoromethyl, trifluoromethoxy, amino, cyano, hydroxy, amino,        carboxy, carbamoyl, sulphamoyl, C₁₋₄alkyl, NR_(p)R_(q), OR_(p),        C(O)R_(p), C(O)OR_(p), OC(O)R_(p), C(O)N(R_(p))R_(q),        N(R_(r))C(O)R_(p), S(O)_(y)R_(p) (where y is 0, 1 or 2),        SO₂N(R_(p))R_(q), N(R_(r))SO₂R_(p) or (CH₂)_(z)NR_(p)R_(q)        (where z is 1, 2 or 3), wherein R_(p) and R_(q) are each        independently selected from hydrogen or C₁₋₄alkyl;        Y is selected from:

-   -   wherein:    -   R_(3a1), R_(3b1), R_(3c1), R_(3d1), R_(3e1), R_(3f1), R_(3g1),        R_(3h1), R_(3i1), R_(3j1), R_(3k1), R_(3l1), R_(3m1), R_(3n1),        R_(3o1), R_(3p1), R_(3q1), R_(3r1) and R_(3s1) are independently        selected from hydrogen (including deuterium), C₁₋₆alkyl, C₃₋₄        cycloalkyl, hydroxy, and halo; and wherein C₁₋₆alkyl, or C₃₋₄        cycloalkyl is optionally substituted with one or more        substituents selected from halo, amino, cyano, and hydroxy;    -   R_(3a2), R_(3b2), R_(3c2), R_(3d2), R_(3e2), R_(3f2), R_(3g2),        R_(3h2), R_(3i2), R_(3j2), R_(3k2), R_(3l2), R_(3m2), R_(3n2),        R_(3o2), R_(3p2), R_(3q2), R_(3r2) and R_(3s2) are hydrogen or        halo;    -   with the proviso that R_(3a1), R_(3b1), R_(3i1), R_(3l1),        R_(3o1), R_(3r1), R_(3a2), R_(3b2), R_(3i2), R_(3l2), R_(3o2)        and R_(3s1) cannot be halo when n=1 or when n=2 and the carbon        atom to which they are attached is linked to an oxygen or        nitrogen atom;    -   or R_(3a1) and R_(3a2), R_(3b1) and R_(3b2), R_(3c1) and        R_(3c2), R_(3d1), and R_(3d2), R_(3e1) and R_(3e2), R_(3f1) and        R_(3f2), R_(3g1) and R_(3g2), R_(3h1) and R_(3h2), R_(3i1) and        R_(3i2), R_(3j1) and R_(3j2), R_(3k1) and R_(3k2), R_(3l1) and        R_(3l2), R_(3m1) and R_(3m2), R_(3n1) and R_(3n2), R_(3o1) and        R_(3o2), R_(3p1) and R_(3p2), R_(3q1) and R_(3q2), or R_(3r1)        and R_(3r2) or R_(3s1) and R_(3s2) may be linked such that,        together with the carbon atom to which they are attached, they        form a spiro-fused C₃₋₄cycloalkyl which is optionally        substituted with one or more substituents selected from halo,        methyl, amino, cyano, and hydroxy;    -   n is 0, 1 or 2        Z is selected from one of the following structures:

wherein:

-   -   B₁ is A₅, wherein A₅ is selected from CR₁₆ and N, wherein R₁₆ is        selected from hydrogen, halo, cyano, C₁₋₄ alkyl, C₂₋₄ alkenyl,        C₂₋₄ alkynyl, a 5- or 6-membered heteroaryl, C₁₋₄ alkoxy,        C₁₋₄haloalkyl, C₁₋₄haloalkoxy, C₃₋₄cycloalkyl, a 3- to        4-membered heterocyclyl and C₃₋₄cycloalkoxy;    -   B₂ is A₆, wherein A₆ is selected from N or CR₁₇, wherein R₁₇,        R_(H2), R_(H4) and R_(H5) are selected from hydrogen, hydroxy,        halo, cyano, C₁₋₅ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄        haloalkoxy, C₂₋₄ alkenyl, C₂₋₄ alkynyl, phenyl, a 5- or        6-membered or heteroaryl, C₃₋₆cycloalkyl, —O—C₃₋₆cycloalkyl,        heterocyclyl, —O-heterocyclyl (carbon-linked),        —(OCH₂CH₂)_(m)—NR_(q)R_(r), —(OCH₂CH₂)_(m)—OCH₃ wherein m is an        integer from 1 to 6, NR_(q)R_(r), —C(O)—NR_(q)R_(r),        —C(O)OR_(q),        -   wherein R_(q) and R_(r) are each independently hydrogen,            C₁₋₅ alkyl, C₃₋₆cycloalkyl, a 3- to 6-membered carbon-linked            heterocyclyl, or R_(q) and R_(r) are linked together such            that, together with the nitrogen atom to which they are            attached, they form a 3- to 6-membered heterocyclic ring;        -   wherein any C₁₋₅alkyl, C₁₋₄ alkoxy, C₂₋₄alkenyl,            C₂₋₄alkynyl, phenyl, 5- or 6-membered or heteroaryl,            C₃₋₆cycloalkyl, —O—C₃₋₆cycloalkyl, heterocyclyl or —O—            heterocyclyl (carbon-linked) is optionally further            substituted by one or more substituents selected from            C₁₋₂alkyl, cyano, C₁₋₂haloalkyl, hydroxy, C₁₋₂alkoxy, halo,            C₁₋₂haloalkoxy, NR_(1ea)R_(1fa) or —S(O)₀₋₂R_(1ea)R_(1fa),            wherein R_(1ea) and Rita are H or C₁₋₂alkyl;        -   B₃ is N or CR_(Z1), wherein R_(Z1) is selected from            hydrogen, C₁₋₄alkyl, cyano, halo, C₁₋₄haloalkyl,            C₁₋₄haloalkoxy, C₁₋₄alkoxy, C₃₋₆cycloalkyl and            —O—C₃₋₆cycloalkyl, wherein C₃₋₆cycloalkyl and            —O—C₃₋₆cycloalkyl are optionally substituted by one or more            of halo, methyl or methoxy;    -   B₄ is selected from C or N;    -   B₅ is selected from CR_(zi1b) or NR_(B5N), wherein:        -   R_(Zi1b) is selected from hydrogen, C₁₋₄alkyl, cyano, halo,            NH₂ and C₁₋₄alkoxy; and        -   R_(B5N) is selected from hydrogen or C₁₋₄alkyl;    -   B₇ is N, NR_(Z2N) or C—R_(Z2), wherein R_(Z2) is selected from        hydrogen, C₁₋₄alkyl, cyano, halo, NH₂ and C₁₋₄alkoxy;    -   B₈ is selected from C or N;    -   with the proviso that no more than four of B₁ to B₈ are N.

Y₂ is A₇, wherein A₇ is selected from CR₁₈ and N; wherein R₁₈ isselected from hydrogen, halo, cyano, C₁₋₄ alkyl, C₁₋₄ alkoxy,C₁₋₄haloalkyl, C₁₋₄haloalkoxy, C₃₋₄cycloalkyl, a 3- to 4-memberedheterocyclyl and C₃₋₄cycloalkoxy;Y₃ is N or CR_(z1a) wherein R_(Z1a), is selected from hydrogen, hydroxy,C₁₋₄alkyl, cyano, halo, C₁₋₄ haloalkyl, C₁₋₄haloalkoxy, C₁₋₄alkoxy,C₃₋₆cycloalkyl and —O—C₃₋₆cycloalkyl, wherein C₃₋₆ cycloalkyl and—O—C₃₋₆cycloalkyl are optionally substituted by one or more of halo,methyl or methoxy;

Y₄ is C or N

Y₅ is CR_(Y5) or NR_(Y5N), wherein:

-   -   R_(Y5) is selected from hydrogen, C₁₋₄alkyl, cyano, halo, NH₂        and C₁₋₄alkoxy;    -   R_(Y5N) is selected from hydrogen or C₁₋₄alkyl;        Y₆ is C—R_(Zi2e) or N, wherein R_(Zi2e) is selected from        hydrogen, C₁₋₄alkyl, cyano, halo, NH₂ and C₁₋₄alkoxy        Y₇ is O, S, CR_(Z2a) or N, wherein R_(Z2a) is selected from        hydrogen, C₁₋₄alkyl, cyano, halo, NH₂ and C₁₋₄alkoxy;

Y₈ Is C or N;

Y₉ is CR_(Z3a) or N; wherein

-   -   R_(Z3a) is selected from hydrogen, C₁₋₄alkyl, cyano, halo, NH₂        and C₁₋₄alkoxy;    -   with the proviso that no more than four of Y₁ to Y_(e) are N.

-   -   X₁ is N or C—R_(Z9), wherein R_(Z9) is selected from hydrogen,        halo, cyano, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄alkoxy, C₁₋₄        haloalkoxy;    -   X₂ is selected from N or CR₄ wherein:        -   R₄ is selected from hydrogen, halo, cyano, C₁₋₄ alkyl, C₁₋₄            haloalkyl, C₁₋₄alkoxy, C₁₋₄ haloalkoxy (e.g. hydrogen, halo,            cyano and methyl);    -   X₃ is N;    -   X₄ is N or C;    -   X₅ is selected from N, CR₅ and CR_(X5a)R_(X5b) wherein:        -   R₅ is selected from hydrogen, halo, cyano, C₁₋₄ alkyl, C₁₋₄            haloalkyl, C₁₋₄alkoxy, C₁₋₄ haloalkoxy (e.g. hydrogen, halo,            cyano and methyl); R_(X5a) and R_(X5b) are independently            selected from hydrogen, halo, cyano, C₁₋₄ alkyl, C₁₋₄            haloalkyl, C₁₋₄alkoxy, C₁₋₄ haloalkoxy (e.g. hydrogen, halo,            cyano and methyl);    -   either:        -   X₆ is A₁ and X₇ is A₂; or        -   X₆ is A₈ and X₇ is A₉ or A₁₁, wherein:        -   A₁ is selected from CR₁₂ and N; wherein            -   R₁₂ is selected from selected from hydrogen, halo,                cyano, C₁₋₄ alkyl,            -   C₁₋₄ haloalkyl, C₁₋₄alkoxy and C₁₋₄ haloalkoxy (e.g.                hydrogen, halo, cyano and C₁₋₄ alkyl);        -   A₂ is selected from CR₁₃ and N, wherein            -   R₁₃ selected from hydrogen, halo, cyano, C₁₋₄ alkyl,                C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy (e.g.                hydrogen, halo, cyano, methoxy and methyl);        -   A₈ is selected from CR₁₉R₂₀ and NR₂₁; wherein            -   R₁₉ and R₂₀ are independently selected from hydrogen,                halo, cyano, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄alkoxy,                C₁₋₄ haloalkoxy (e.g hydrogen, halo, cyano and C₁₋₄                alkyl);            -   R₂₁ is hydrogen or C₁₋₄alkyl.        -   A₉ is selected from CR₂₂R₂₃ and NR₂₄;            -   wherein R₂₂ and R₂₃ are independently selected from                selected from hydrogen, halo, cyano, C₁₋₄ alkyl, C₁₋₄                haloalkyl, C₁₋₄alkoxy, C₁₋₄ haloalkoxy (e.g. hydrogen,                halo, cyano and methyl);            -   R₂₄ is selected from hydrogen or C₁₋₄alkyl        -   A₁₁ is selected from CR₂₈R₂₉ and NR₃₀;            -   R₂₈ and R₂₉ are selected from hydrogen, halo, methoxy                and methyl;            -   R₃₀ is selected from hydrogen or C₁₋₄alkyl.    -   X₈ is selected from CR₆, N or CR_(X6a)R_(X6b);        -   wherein R₆ is selected from hydrogen, halo, cyano, C₁₋₄            alkyl, C₁₋₄ haloalkyl, C₁₋₄alkoxy and C₁₋₄ haloalkoxy;        -   R_(X6a) and R_(X6b) are each independently selected from            hydrogen, halo, cyano, C₁₋₄ alkyl, C₁₋₄ haloalkyl,            C₁₋₄alkoxy and C₁₋₄ haloalkoxy;    -   X₉ is N or C;    -   with the proviso that no more than four of X₂ to X₉ are N.

Z₁₀ is N or C—R_(Z10), wherein R_(Z10) is selected from hydrogen, halo,cyano, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄alkoxy, C₁₋₄ haloalkoxy;Z₁₁ is N or C—R_(Z11), wherein R_(Z11) is selected from hydrogen, halo,cyano, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄alkoxy, C₁₋₄ haloalkoxy;Z₁₂ is N or C—R_(Z12), wherein R_(Z12) is selected from hydrogen, halo,cyano, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄alkoxy, C₁₋₄ haloalkoxy;Z₁₃ is N or C—R_(Z13), wherein R_(Z13) is selected from hydrogen, halo,cyano, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄alkoxy, C₁₋₄ haloalkoxy;Z₁₄ is N or C—R_(Z14), wherein R_(Z14) is selected from hydrogen, halo,cyano, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄alkoxy, C₁₋₄ haloalkoxy;Z₁₅ is N or C—R_(Z15), wherein R_(Z15) is selected from hydrogen, halo,cyano, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄alkoxy, C₁₋₄ haloalkoxy;Z₁₆ is N or C—R_(Z16), wherein R_(Z16) is selected from hydrogen, halo,cyano, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄alkoxy, C₁₋₄ haloalkoxy;with the proviso that no more than three of Z₁₀ to Z₁₆ are N;

-   -   Q₇ is CR₇ or N;    -   Q₈ is CR₈ or N;    -   Q₉ is CR₉ or N;    -   Q₁₀ is CR₁₀ or N;    -   Q₁₁ is CR₁₁ or N;    -   Q_(11a) is NR_(11N) or CR_(11a)R_(11b);        wherein R₇, R₈, R₉, R₁₀, R₁₁, R_(11a) and R_(11b) are each        independently selected from hydrogen, NH₂, halo, cyano, C₁₋₄        alkoxy, C₁₋₄ haloalkoxy, C₁₋₆ alkyl, —CH₂OCH₃, —CH₂SO₂CH₃,        —SO₂CH₃, —NHC(O)CH₃ and —C(O)NR_(v1)R_(v2), wherein R_(v1) and        R_(v2) are independently selected from hydrogen and methyl and;        and R_(11N) is selected from hydrogen, NH₂, halo, cyano, and        C₁₋₆ alkyl; or    -   R₉ and R₁₀ may be linked together such that, together to the        atoms to which they are attached, they form a fused 5- or        6-membered saturated or unsaturated ring system, or R₁₀ and R₁₁        may be linked together such that, together to the atoms to which        they are attached, they form a fused 5- or 6-membered saturated        or unsaturated ring system, wherein either of the fused 5- or        6-membered saturated or unsaturated ring system may be        optionally substituted by one or more substituents selected from        C₁₋₂alkyl, cyano, C₁₋₂haloalkyl, hydroxy, C₁₋₂alkoxy, halo,        C₁₋₂haloalkoxy, NR_(1ia)R_(1ja) or —S(O)₀₋₂R_(1ia)R_(1ja),        wherein R_(1ia) and R_(1ja) are H or C₁₋₂alky;        with the proviso that no more than three of Q₇ to Q₁₁ are N.        2. A compound of Formula (I) according to paragraph 1, or a        pharmaceutically acceptable salt thereof,

X—Y—Z  (I)

wherein:X is selected from:

whereinQ₁ is selected from NH, N—C₁₋₄alkyl, O or S;Q₂₁ is selected from N or CR₂a;Q_(2b) is selected from N or CR_(2b);Q_(2c) is selected from N or CR₂c;Q_(2d) is selected from N or CR_(2d);Q₃ is selected from N or CR_(1b);Q₄ is selected from N or CR_(1x);subject to the proviso that no more than 3 of Q₁, Q_(2a), Q_(2b),Q_(2c), Q_(2d), Q₃ and Q₄ are nitrogen;R_(1a) is selected from:

-   -   (i) C₁₋₄alkyl or C₁₋₄alkoxy, each of which being optionally        substituted by halo, cyano, hydroxy, C₃₋₆cycloalkyl, a 3 to 6        membered heterocyclyl C₁₋₄alkoxy, C₁₋₄haloalkoxy, aryl or        heteroaryl; or    -   (ii) a group of the formula:

—(CR_(1c)R_(1d))_(p)—NR_(1e)R_(1f);

-   -   wherein        -   p is an integer selected from 0, 1, 2 or 3        -   R_(1c) and R_(1d) are independently selected from:            -   (i) hydrogen (including deuterium),            -   (ii) C₁₋₆alkyl which is optionally substituted by one                more substituents selected from cyano, oxo, hydroxy,                C₁₋₄alkoxy, halo, C₁₋₄haloalkoxy, C₃₋₆cycloalkyl,                —O—C₃₋₆cycloalkyl, NR_(1ca)R_(1da) or                —S(O)₀₋₂R_(1ca)R_(1da), wherein R_(1ca) and R_(1da) are                H or C₁₋₂alkyl; and wherein C₃₋₆cycloalkyl and —O—C₃₋₆                cycloalkyl are optionally further substituted with halo,                cyano or hydroxy;            -   (iii) C₃₋₄cycloalkyl or 3 to 5 membered heterocyclyl,                each of which is optionally substituted by C₁₋₄alkyl,                C₁₋₄haloalkyl, cyano, hydroxy, C₁₋₂alkoxy, halo,                C₁₋₂haloalkoxy, NR_(1ca)R_(1da) or                —S(O)₀₋₂R_(1ca)R_(1da), wherein R_(1ca) and R_(1da) are                H or C₁₋₂alkyl; and;            -   (iv) or R_(1c) and R_(1d) are linked together such that,                together with the carbon atom to which they are                attached, they form a 3- to 6-membered cycloalkyl or                heterocyclic ring, or a spirocyclic ring system, each of                which is optionally substituted by one or more                substituents selected from C₁₋₂alkyl, C₁₋₂haloalkyl,                cyano, hydroxy, C₁₋₂alkoxy, halo, C₁₋₂haloalkoxy,                NR_(1ca)R_(1da) or —S(O)₀₋₂R_(1ca)R_(1da), wherein                R_(1ca) and R_(1da) are H or C₁₋₂alkyl;    -   R_(1e) and R_(1f) are each independently selected from:        -   (i) hydrogen (including deuterium);        -   (ii) C₁₋₆alkyl which is optionally substituted by one more            substituents selected from cyano, oxo, hydroxy, C₁₋₂alkoxy,            halo, C₁₋₂haloalkoxy, NR_(1ea)R_(1fa) or            —S(O)₀₋₂R_(1ea)R_(1fa), wherein R_(1ea) and R_(1fe) are H or            C₁₋₂alkyl;        -   (iii) a group with the formula:

—(CR_(1g)R_(1h))_(q)-T₁

-   -   -   -   wherein:            -   q is 0, 1, 2, 3, 4, 5 or 6;

        -   R_(1g) and R_(1h) are independently selected from:            -   a) hydrogen;            -   b) C₁₋₆alkyl which is optionally substituted by one more                substituents selected from cyano, hydroxy, C₁₋₄alkoxy,                halo, C₁₋₄-haloalkoxy, —O—C₃₋₆cycloalkyl,                NR_(1ga)R_(1ha) or —S(O)₀₋₂R_(1ga)R_(1ha), wherein                R_(1ga) and R_(1ha) are H or C₁₋₂alkyl; and wherein                —O—C₃₋₆cycloalkyl is optionally substituted with halo,                cyano or hydroxy;            -   c) an aryl-C₁₋₆alkyl, heteroarylC₁₋₆alkyl,                C₃₋₆cycloalkyl or C₃₋₆cycloalkylC₁₋₆alkyl group, each of                which is optionally substituted by one or more                substituents selected from C₁₋₂alkyl, cyano,                C₁₋₂-haloalkyl, hydroxy, C₁₋₂alkoxy, halo,                C₁₋₂haloalkoxy, NR_(1ga)R_(1ha) or                —S(O)₀₋₂R_(1ga)R_(1ha), wherein R_(1ga) and R_(1ha) are                H or C₁₋₂alkyl; or            -   d) or R_(1g) and R_(1h) are optionally linked together                such that, together with the carbon atom to which they                are attached, they form a 3- to 6-membered cycloalkyl or                heterocyclic ring which is optionally substituted by one                or more substituents selected from C₁₋₂alkyl, cyano,                C₁₋₂haloalkyl, hydroxy, C₁₋₂alkoxy, halo,                C₁₋₂haloalkoxy, NR_(1ga)R_(1ha) or                —S(O)₀₋₂R_(1ga)R_(1ha), wherein R_(1ga) and R_(1ha) are                H or C₁₋₂alkyl; and            -   T₁ is selected from hydrogen, halo, C₁₋₄alkyl,                C₁₋₄haloalkyl, cyano, hydroxy, NR_(1t)R_(2t) or                —S(O)₀₋₂R_(1t)R_(2t) (wherein R_(1t) and R_(2t) are H or                C₁₋₄alkyl), C₃₋₈cycloalkyl, C₂₋₃alkenyl, C₂₋₃alkynyl,                aryl, heterocyclyl, a mono- or bicyclic heteroaryl, a                spirocyclic carbocyclic or heterocyclic ring system, a                bridged C₃₋₆cycloalkyl, a bridged bicyclic                C₅₋₁₂cycloalkyl, or a bridged heterocyclic ring system,                each of which is optionally substituted by one or more                substituents selected from C₁₋₂alkyl, C₁₋₂haloalkyl,                cyano, hydroxy, C₁₋₂alkoxy, halo, C₁₋₂-haloalkoxy,                C₃₋₆cycloalkyl, NR_(3t)R_(4t) or —S(O)₀₋₂R_(3t)R_(4t),                wherein R_(3t) and R_(4t) are H or C₁₋₂alkyl;

        -   (iv) or R_(1e) and R_(1f) are linked such that, together            with the nitrogen atom to which they are attached, they form            a mono- or bicyclic-heterocyclic ring, which is optionally            substituted by one or more substituents selected from            C₁₋₄alkyl, C₁₋₄haloalkyl, C₃₋₆cycloalkyl, cyano, hydroxy,            C₁₋₄alkoxy, halo, C₁₋₄ haloalkoxy, NR_(1i)R_(1j) or            —S(O)₀₋₂R_(1i)R_(1j), wherein R_(1i) and R_(1j) are H or            C₁₋₄alkyl, and/or the mono- or bicyclic hetereocyclic ring            formed by R_(1e) and R_(1f) is optionally spiro-fused to a            C₃₋₆cycloalkyl or a heterocyclic ring, which in turn is            optionally substituted by one or more substituents selected            from C₁₋₄ alkyl, C₁₋₄haloalkyl, C₃₋₆cycloalkyl, cyano,            hydroxy, C₁₋₄alkoxy, halo, C₁₋₄ haloalkoxy, NR_(1i)R_(1j) or            —S(O)₀₋₂R_(1i)R_(1j), wherein R_(1i) and R_(1j) are H or            C₁₋₄alkyl; wherein any wherein any alkyl, alkoxy or            C₃₋₆cycloalkyl is further optionally substituted by one or            more substituents selected from cyano, hydroxy, halo,            NR_(1k)R_(1l) or —S(O)₀₋₂R_(1k)R_(1l), wherein R_(1k) and            R_(1l) are H or C₁₋₄alkyl            R_(1b) is selected from hydrogen, cyano, halo or C₁₋₃ alkyl;            R_(1x) is selected from hydrogen, cyano, halo or C₁₋₃ alkyl;            R_(2a), R_(2b), R_(2c) and R_(2d) are independently selected            from hydrogen, cyano, halo or a group of the formula:

-L_(2a)-L_(2b)-Q₂

wherein

-   -   L_(2a) is absent or C₁₋₃alkylene optionally substituted by C₁₋₂        alkyl or oxo;    -   L_(2b) is absent or selected from O, S, SO, SO₂, N(R_(n)), C(O),        C(O)O, OC(O), C(O)N(R_(n)), N(R_(n))C(O), N(R_(n))C(O)N(R_(o)),        S(O)₂N(R_(n)), or N(R_(n))SO₂, wherein R_(n) and R_(o) are each        independently selected from hydrogen or C₁₋₂alkyl; and    -   Q₂ is hydrogen, cyano, C₁₋₆alkyl, C₃₋₆cycloalkyl, aryl,        heterocyclyl or heteroaryl, each of which is optionally        substituted by one or more substituents selected from halo,        trifluoromethyl, trifluoromethoxy, amino, cyano, hydroxy, amino,        carboxy, carbamoyl, sulphamoyl, C₁₋₄alkyl, NR_(p)R_(q), OR_(p),        C(O)R_(p), C(O)OR_(p), OC(O)R_(p), C(O)N(R_(p))R_(q),        N(R_(r))C(O)R_(p), S(O)_(y)R_(p) (where y is 0, 1 or 2),        SO₂N(R_(p))R_(q), N(R_(r))SO₂R_(p) or (CH₂)_(z)NR_(p)R_(q)        (where z is 1, 2 or 3), wherein R_(p) and R_(q) are each        independently selected from hydrogen or C₁₋₄alkyl;        Y is selected from:

-   -   wherein:    -   R_(3a1), R_(3b1), R_(3c1), R_(3d1), R_(3e1), R_(3f1), R_(3g1),        R_(3h1), R_(3i1), R_(3j1), R_(3k1), R_(3l1), R_(3m1), R_(3n1),        R_(3o1), R_(3p1), R_(3q1), R_(3r1) and R_(3s1) are independently        selected from hydrogen (including deuterium), C₁₋₆alkyl, C₃₋₄        cycloalkyl, hydroxy, and halo; and wherein C₁₋₆alkyl, or C₃₋₄        cycloalkyl is optionally substituted with one or more        substituents selected from halo, amino, cyano, and hydroxy;    -   R_(3a2), R_(3b2), R_(3c2), R_(3d2), R_(3e2), R_(3f2), R_(3g2),        R_(3h2), R_(3i2), R_(3j2), R_(3k2), R_(3l2), R_(3m2), R_(3n2),        R_(3o2), R_(3p2), R_(3q2), R_(3r2) and R_(3s2) are hydrogen or        halo;    -   with the proviso that R_(3a1), R_(3b1), R_(3i1), R_(3l1),        R_(3o1), R_(3r1), R_(3a2), R_(3b2), R_(3i2), R_(3l2), R_(3o2)        and R_(3s1) cannot be halo when n=1 or when n=2 and the carbon        atom to which they are attached is linked to an oxygen or        nitrogen atom;    -   or R_(3a1) and R_(3a2), R_(3b1) and R_(3b2), R_(3c1) and        R_(3c2), R_(3d1) and R_(3d2), R_(3e1) and R_(3e2), R_(3f1) and        R_(3f2), R_(3g1) and R_(3g2), R_(3h1) and R_(3h2), R_(3i1) and        R_(3i2), R_(3j1) and R_(3j2), R_(3k1) and R_(3k2), R_(3l1) and        R_(3l2), R_(3m1) and R_(3m2), R_(3n1) and R_(3n2), R_(3o1) and        R_(3o2), R_(3p1) and R_(3p2), R_(3q1) and R_(3q2), or R_(3r1)        and R_(3r2) or R_(3s1) and R_(3s2) may be linked such that,        together with the carbon atom to which they are attached, they        form a spiro-fused C₃₋₄cycloalkyl which is optionally        substituted with one or more substituents selected from halo,        methyl, amino, cyano, and hydroxy;    -   n is 0, 1 or 2        Z is selected from:

-   -   wherein:    -   R₄ is selected from hydrogen, halo, cyano, C₁₋₄ alkyl, C₁₋₄        haloalkyl, C₁₋₄alkoxy, C₁₋₄ haloalkoxy (e.g. hydrogen, halo,        cyano and methyl);    -   R₅ is selected from hydrogen, halo, cyano, C₁₋₄ alkyl, C₁₋₄        haloalkyl, C₁₋₄alkoxy, C₁₋₄ haloalkoxy (e.g. hydrogen, halo,        cyano and methyl);    -   R₆ is selected from hydrogen, halo, cyano, C₁₋₄ alkyl, C₁₋₄        haloalkyl, C₁₋₄alkoxy, C₁₋₄ haloalkoxy (e.g. hydrogen, halo,        cyano and methyl);    -   R₈, R₉, R₁₀ and R₁₁ are independently selected from hydrogen,        NH₂, halo, cyano, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, C₁₋₆ alkyl,        —CH₂OCH₃, —CH₂SO₂CH₃, —SO₂CH₃, —NHC(O)CH₃ and        —C(O)NR_(v1)R_(v2), wherein R_(v1) and R_(v2) are independently        selected from hydrogen and methyl; or    -   R₉ and R₁₀ may be linked together such that, together to the        atoms to which they are attached, they form a fused 5- or        6-membered saturated or unsaturated ring system, or R₁₀ and R₁₁        may be linked together such that, together to the atoms to which        they are attached, they form a fused 5- or 6-membered saturated        or unsaturated ring system, wherein either of the fused 5- or        6-membered saturated or unsaturated ring system may be        optionally substituted by one or more substituents selected from        C₁₋₂alkyl, cyano, C₁₋₂haloalkyl, hydroxy, C₁₋₂alkoxy, halo,        C₁₋₂haloalkoxy, NR_(1ia)R_(1ja) or —S(O)₀₋₂R_(1ia)R_(1ja),        wherein R_(1ia) and R_(1ja) are H or C₁₋₂alky;    -   R₇ and R_(11N) are independently selected from hydrogen, NH₂,        halo, cyano, and C₁₋₆ alkyl;    -   R_(Z1) and R_(Z1a) selected from hydrogen, C₁₋₄alkyl, cyano,        halo, C₁₋₄haloalkyl, C₁₋₄ haloalkoxy, C₁₋₄alkoxy, C₃₋₆cycloalkyl        and —O—C₃₋₆cycloalkyl, wherein C₃₋₆cycloalkyl and        —O—C₃₋₆cycloalkyl are optionally substituted by one or more of        halo, methyl or methoxy;    -   R_(Z2) and R_(Z2a) are selected from hydrogen, C₁₋₄alkyl, cyano,        halo, NH₂ and C₁₋₄alkoxy;    -   R_(Z3a) is selected from hydrogen, C₁₋₄alkyl, cyano, halo, NH₂        and C₁₋₄alkoxy;    -   R_(Zi1b) is selected from hydrogen, C₁₋₄alkyl, cyano, halo, NH₂        and C₁₋₄alkoxy;    -   R_(Zi2e) is selected from hydrogen, C₁₋₄alkyl, cyano, halo, NH₂        and C₁₋₄alkoxy;    -   R_(Y5N) and R_(Z2N) are selected from hydrogen or C₁₋₄alkyl;    -   R_(Z9) is selected from hydrogen, halo, cyano, C₁₋₄ alkyl, C₁₋₄        haloalkyl, C₁₋₄alkoxy, C₁₋₄ haloalkoxy;    -   R_(Z10) is selected from hydrogen, halo, cyano, C₁₋₄ alkyl, C₁₋₄        haloalkyl, C₁₋₄alkoxy, C₁₋₄ haloalkoxy;    -   R_(Z11) is selected from hydrogen, halo, cyano, C₁₋₄ alkyl, C₁₋₄        haloalkyl, C₁₋₄alkoxy, C₁₋₄ haloalkoxy;    -   R_(Z12) is selected from hydrogen, halo, cyano, C₁₋₄ alkyl, C₁₋₄        haloalkyl, C₁₋₄alkoxy, C₁₋₄ haloalkoxy;    -   R_(Z13) is selected from hydrogen, halo, cyano, C₁₋₄ alkyl, C₁₋₄        haloalkyl, C₁₋₄alkoxy, C₁₋₄ haloalkoxy;    -   R_(Z14) is selected from hydrogen, halo, cyano, C₁₋₄ alkyl, C₁₋₄        haloalkyl, C₁₋₄alkoxy, C₁₋₄ haloalkoxy;    -   R_(Z15) is selected from hydrogen, halo, cyano, C₁₋₄ alkyl, C₁₋₄        haloalkyl, C₁₋₄alkoxy, C₁₋₄ haloalkoxy;    -   R_(Z16) is selected from hydrogen, halo, cyano, C₁₋₄ alkyl, C₁₋₄        haloalkyl, C₁₋₄alkoxy, C₁₋₄ haloalkoxy;    -   A₁ is selected from CR₁₂ and N;    -   A₂ is selected from CR₁₃ and N;    -   A₅ is selected from CR₁₆ and N;    -   A₆ is selected from CR₁₇ and N;    -   A₇ is selected from CR₁₈ and N;    -   A₈ is selected from CR₁₉R₂₀ and NR₂₁;    -   A₉ is selected from CR₂₂R₂₃ and NR₂₄;    -   A₁₁ is selected from CR₂₈R₂₉ and NR₃₀;    -   R₁₂ is selected from hydrogen, halo, cyano, C₁₋₄ alkyl, C₁₋₄        haloalkyl, C₁₋₄alkoxy, C₁₋₄ haloalkoxy (e.g. hydrogen, halo,        cyano and C₁₋₄ alkyl);    -   R₁₃ is selected from hydrogen, halo, cyano, C₁₋₄ alkyl, C₁₋₄        haloalkyl, C₁₋₄alkoxy, C₁₋₄ haloalkoxy (e.g. hydrogen, halo,        cyano, methoxy and methyl);    -   R₁₆ and R₁₈ are selected from hydrogen, halo, cyano, C₁₋₄ alkyl,        C₁₋₄ alkoxy, C₁₋₄haloalkyl, C₁₋₄haloalkoxy, C₃₋₄cycloalkyl, a 3-        to 4-membered heterocyclyl and C₃₋₄-cycloalkoxy;    -   R₁₇ is selected from hydrogen, halo, cyano, C₁₋₄ alkyl, C₁₋₄        haloalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, C₂₋₄ alkenyl, C₂₋₄        alkynyl, phenyl, a 5- or 6-membered or heteroaryl,        C₃₋₆cycloalkyl, —O—C₃₋₆cycloalkyl, heterocyclyl, —O-heterocyclyl        (carbon-linked), —(OCH₂CH₂)_(m)—OCH₃ wherein m is an integer        from 1 to 6, NR_(q)R_(r), wherein R_(q) and R_(r) are each        independently hydrogen, C₁₋₅ alkyl, C₃₋₆cycloalkyl, a 3- to        6-membered carbon-linked heterocyclyl, or R_(q) and R_(r) are        linked together such that, together with the nitrogen atom to        which they are attached, they form a 3- to 6-membered        heterocyclic ring; wherein any C₁₋₅alkyl, C₁₋₄ alkoxy,        C₂₋₄alkenyl, C₂₋₄alkynyl, phenyl, 5- or 6-membered or        heteroaryl, C₃₋₆cycloalkyl, —O—C₃₋₆cycloalkyl, heterocyclyl or        —O— heterocyclyl (carbon-linked) is optionally further        substituted by one or more substituents selected from C₁₋₂alkyl,        cyano, C₁₋₂haloalkyl, hydroxy, C₁₋₂alkoxy, halo, C₁₋₂haloalkoxy,        NR_(1ea)R_(1fa) or —S(O)₀₋₂R_(1ea)R_(1fa), wherein R_(1ea) and        R_(1fa) are H or C₁₋₂alkyl; R₁₉ and R₂₀, R₂₅ and R₂₆ are        selected from hydrogen, halo, cyano and C₁₋₄ alkyl; R₂₂ and R₂₃        are selected from hydrogen, halo, cyano, C₁₋₄ alkyl, C₁₋₄        haloalkyl, C₁₋₄alkoxy, C₁₋₄ haloalkoxy (e.g. hydrogen, halo,        cyano and methyl;    -   R₂₈ and R₂₉ are selected from hydrogen, halo, methoxy and        methyl;    -   R₂₁, R₂₄ and R₃₀ are hydrogen or C₁₋₄alkyl.        3. A compound according to paragraph 1 or 2, wherein X is        selected from:

wherein Q₁, R_(1a), R_(1b), R_(1x), R_(2a), R_(2b), R_(2c), R_(2d) areas defined in paragraph 1.3. A compound according to paragraph 1 2, or a pharmaceuticallyacceptable salt thereof, wherein X is selected from:

wherein Q₁, R_(1a), R_(1b), R_(2a), R_(2b), R_(2e) and R_(2d) are asdefined in paragraph 1.4. A compound according to any one of the preceding paragraphs, or apharmaceutically acceptable salt thereof, wherein X is selected from:

-   -   wherein Q₁, R_(1a), R_(1b), R_(2a), R_(2b) and R_(2d) are as        defined in paragraph 1.        5. A compound according to any one of the preceding paragraphs,        or a pharmaceutically acceptable salt thereof, wherein X is:

-   -   wherein Q₁, R_(1a), R_(1b), R_(2a), R_(2b) and R_(2d) are as        defined in paragraph 1.        6. A compound according to any one of paragraphs 1 to 3, or a        pharmaceutically acceptable salt thereof, wherein Q₁ is selected        from NH or N—C₁₋₄alkyl.        7. A compound according to paragraph 1 or paragraph 2, or a        pharmaceutically acceptable salt thereof, wherein X is selected        from:

-   -   wherein R_(1a) is as defined in paragraph 1 or paragraph 2.        8. A compound according to any preceding paragraph, or a        pharmaceutically acceptable salt thereof, wherein R_(1a) is        selected from:    -   (i) C₁₋₄alkyl optionally substituted by halo, cyano, hydroxy,        C₃₋₆cycloalkyl, a 3 to 6 membered heterocyclyl, C₁₋₄alkoxy,        C₁₋₄haloalkoxy, aryl or heteroaryl; or    -   (ii) a group of the formula:

—(CR_(1c)R_(1d))_(p)—NR_(1e)R_(1f);

-   -   wherein        -   p is an integer selected from 1 or 2;    -   R_(1c) and R_(1d) are independently selected from:        -   (i) hydrogen (including deuterium),        -   (ii) C₁₋₃alkyl which is optionally substituted by one more            substituents selected from cyano, oxo, hydroxy, C₁₋₄alkoxy,            halo, C₁₋₄haloalkoxy, —O—C₃₋₆cycloalkyl, NR_(1ca)R_(1da) or            —S(O)₀₋₂R_(1ca)R_(1da), wherein R_(1ca) and R_(1da) are H or            C₁₋₂alkyl; and wherein C₃₋₆cycloalkyl and —O—C₃₋₆cycloalkyl            are optionally substituted with halo, cyano or hydroxy;        -   (iii) C₃₋₄cycloalkyl or 3 to 5 membered heterocyclyl, each            of which is optionally substituted by C₁₋₄alkyl,            C₁₋₄haloalkyl, cyano, hydroxy, C₁₋₂alkoxy, halo,            C₁₋₂haloalkoxy, NR_(1ca)R_(1da) or —S(O)₀₋₂R_(1ca)R_(1da),            wherein R_(1ca) and R_(1da) are H or C₁₋₂alkyl; and;        -   (iv) or R_(1c) and R_(1d) are linked together such that,            together with the carbon atom to which they are attached,            they form a 3- to 5-membered cycloalkyl or heterocyclic            ring, or a spirocyclic ring system, each of which is            optionally substituted by one or more substituents selected            from C₁₋₂alkyl, C₁₋₂haloalkyl, cyano, hydroxy, C₁₋₂alkoxy,            halo, C₁₋₂-haloalkoxy, NR_(1ca)R_(1da) or            —S(O)₀₋₂R_(1ca)R_(1da), wherein R_(1ca) and R_(1da) are H or            C₁₋₂alkyl;    -   R_(1e) and R_(1f) are each independently selected from:        -   (i) hydrogen (including deuterium);        -   (ii) C₁₋₆alkyl which is optionally substituted by one more            substituents selected from cyano, oxo, hydroxy, C₁₋₂alkoxy,            halo, C₁₋₂haloalkoxy, NR_(1ea)R_(1fa) or            —S(O)₀₋₂R_(1ea)R_(1fa), wherein R_(1ea) and R_(1fa) are H or            C₁₋₂alkyl;        -   (iii) a group with the formula:

—(CR_(1g)R_(1h))_(q)-T₁

-   -   -   -   wherein:            -   q is 0, 1, 2 or 3;            -   R_(1g) and R_(1h) are independently selected from:                -   a) hydrogen (including deuterium); or                -   b) C₁₋₃alkyl which is optionally substituted by one                    more substituents selected from cyano, oxo, hydroxy,                    C₁₋₃alkoxy, halo, C₁₋₄haloalkoxy, —O—C₃₋₄cycloalkyl,                    wherein —O—C₃₋₄cycloalkyl is optionally substituted                    with halo, cyano or hydroxy, NR_(1ca)R_(1da) or                    —S(O)₀₋₂R_(1ca)R_(1da), wherein R_(1ca) and R_(1da)                    are H or C₁₋₂alkylNR_(1ga)R_(1ha) or                    —S(O)₀₋₂R_(1ga)R_(1ha), wherein R_(1ga) and R_(1ha)                    are H or C₁₋₂alkyl;                -   c) or R_(1g) and R_(1h) are optionally linked                    together such that, together with the carbon atom to                    which they are attached, they form a 3- to                    6-membered cycloalkyl or heterocyclic ring which is                    optionally substituted by one or more substituents                    selected from C₁₋₂alkyl, C₁₋₂-haloalkyl, cyano,                    hydroxy, C₁₋₂alkoxy, halo, C₁₋₂ haloalkoxy,                    NR_(1ga)R_(1ha) or —S(O)₀₋₂R_(1ga)R_(1ha), wherein                    Riga and R_(1ha) are H or C₁₋₂alkyl;            -   and T₁ is selected from hydrogen, halo, C₁₋₄alkyl,                C₁₋₄haloalkyl, cyano, hydroxy, NR_(1t)R_(2t) or                —S(O)₀₋₂R_(1t)R_(2t) (wherein R_(1t) and R_(2t) are H or                C₁₋₄alkyl), C₃₋₈cycloalkyl, C₂₋₃alkenyl, C₂₋₃alkynyl,                aryl, heterocyclyl, a mono- or bicyclic heteroaryl, a                spirocyclic carbocyclic or heterocyclic ring system, a                bridged C₃₋₈cycloalkyl, a bridged bicyclic                C₅₋₁₂cycloalkyl, or a bridged heterocyclic ring system,                each of which is optionally substituted by one or more                substituents selected from C₁₋₂alkyl, C₁₋₂haloalkyl,                cyano, hydroxy, C₁₋₂alkoxy, halo, C₁₋₂haloalkoxy,                C₃₋₆cycloalkyl, NR_(3t)R_(4t) or —S(O)₀₋₂R_(3t)R_(4t),                wherein R_(3t) and R_(4t) are H or C₁₋₂alkyl;

        -   (iv) or R_(1e) and R_(1f) are linked such that, together            with the nitrogen atom to which they are attached, they form            a mono- or bicyclic-heterocyclic ring, which is optionally            substituted by one or more substituents selected from            C₁₋₄alkyl, C₁₋₄haloalkyl, C₃₋₆cycloalkyl, cyano, hydroxy,            C₁₋₄alkoxy, halo, C₁₋₄haloalkoxy, NR_(1i)R_(1j) or            —S(O)₀₋₂R_(1i)R_(1j), wherein R_(1i) and R_(1j) are H or            C₁₋₄alkyl, and/or the mono- or bicyclic hetereocyclic ring            formed by R_(1e) and R_(1f) is optionally spiro-fused to a            C₃₋₆cycloalkyl or a heterocyclic ring, which in turn is            optionally substituted by one or more substituents selected            from C₁₋₄alkyl, C₁₋₄haloalkyl, C₃₋₆cycloalkyl, cyano,            hydroxy, C₁₋₄alkoxy, halo, C₁₋₄haloalkoxy, NR_(1i)R_(1j) or            —S(O)₀₋₂R_(1i)R_(1j), wherein R_(1i) and R_(1j) are H or            C₁₋₄alkyl;            -   wherein any wherein any alkyl, alkoxy or C₃₋₆cycloalkyl                is further optionally substituted by one or more                substituents selected from cyano, hydroxy, halo,                NR_(1k)R_(1l) or —S(O)₀₋₂R_(1k)R_(1l), wherein R_(1k)                and R_(1l) are H or C₁alkyl.                9. A compound according to any preceding paragraph, or a                pharmaceutically acceptable salt thereof, wherein R_(1a)                is a group of the formula:

—(CR_(1c)R_(1d))_(p)—NR_(1e)R_(1f)

whereinp is an integer selected from 1 or 2;R_(1c) and R_(1d) are independently selected from:

-   -   (i) hydrogen (including deuterium),    -   (ii) C₁₋₃alkyl which is optionally substituted by one more        substituents selected from cyano, oxo, hydroxy, C₁₋₃alkoxy,        halo, C₁₋₄₃haloalkoxy, —O—C₃₋₄cycloalkyl, or NH₂; wherein        —O—C₃₋₆cycloalkyl is optionally substituted with halo, cyano or        hydroxy,    -   (iii) or R_(1c) and R_(1d) are linked together such that,        together with the carbon atom to which they are attached, they        form a 3- to 5-membered cycloalkyl or heterocyclic ring, or a        spirocyclic ring system, each of which is optionally substituted        by one or more substituents selected from C₁₋₂alkyl,        C₁₋₂haloalkyl, cyano, hydroxy, C₁₋₂alkoxy, halo, C₁₋₂haloalkoxy,        NR_(1ca)R_(1da) or —S(O)₀₋₂R_(1ca)R_(1da), wherein R_(1ca) and        R_(1da) are H or C₁₋₂alkyl;        R_(1e) is selected from:    -   (i) hydrogen (including deuterium);    -   (ii) C₁₋₃alkyl which is optionally substituted by one more        substituents selected from cyano, oxo, hydroxy, C₁₋₂alkoxy,        halo, C₁₋₂haloalkoxy and NH₂;        and R_(1f) is selected from:    -   (i) C₁₋₆alkyl which is optionally substituted by one more        substituents selected from cyano, oxo, hydroxy, C₁₋₂alkoxy,        halo, C₁₋₂haloalkoxy and NH₂;    -   (ii) a group with the formula:

—(CR_(1g)R_(1h))_(q)-T₁

-   -   -   wherein:        -   q is 1, 2 or 3;

    -   R_(1g) and R_(1h) are independently selected from:        -   a) hydrogen (including deuterium); or        -   b) C₁₋₆alkyl which is optionally substituted by one more            substituents selected from cyano, oxo, hydroxy, C₁₋₄alkoxy,            halo, C₁₋₄haloalkoxy, —O—C₃₋₆cycloalkyl, NR_(1ca)R_(1da) or            —S(O)₀₋₂R_(1ca)R_(1da), wherein R_(1ca) and R_(1da) are H or            C₁₋₂alkylNR_(1ga)R_(1ha) or —S(O)₀₋₂R_(1ga)R_(1ha), wherein            R_(1ga) and R_(1ha) are H or C₁₋₂alkyl; and wherein            —O—C₃₋₆cycloalkyl is optionally substituted with halo, cyano            or hydroxy;        -   c) or R_(1g) and R_(1h) are optionally linked together such            that, together with the carbon atom to which they are            attached, they form a 3- to 4-membered cycloalkyl or            heterocyclic ring which is optionally substituted by one or            more substituents selected from C₁₋₂alkyl, C₁₋₂-haloalkyl,            cyano, hydroxy, C₁₋₂alkoxy, halo, C₁₋₂-haloalkoxy,            NR_(1ga)R_(1h)a or —S(O)₀₋₂R_(1ga)R_(1ha), wherein R_(1ga)            and R_(1ha) are H or C₁₋₂alkyl;

    -   and T₁ is selected from hydrogen, halo, C₁₋₄alkyl,        C₁₋₄haloalkyl, cyano, hydroxy, NR_(1t)R_(2t) or        —S(O)₀₋₂R_(1t)R_(2t) (wherein R_(1t) and R_(2t) are H or        C₁₋₄alkyl), C₃₋₈cycloalkyl, C₂₋₃alkenyl, C₂₋₃alkynyl, aryl,        heterocyclyl, a mono- or bicyclic heteroaryl, a spirocyclic        carbocyclic or heterocyclic ring system, a bridged        C₃₋₈cycloalkyl, a bridged bicyclic C₅₋₁₂cycloalkyl, or a bridged        heterocyclic ring system, each of which is optionally        substituted by one or more substituents selected from C₁₋₂alkyl,        C₁₋₂-haloalkyl, cyano, hydroxy, C₁₋₂alkoxy, halo,        C₁₋₂haloalkoxy, C₃₋₆cycloalkyl, NR_(3t)R_(4t) or        —S(O)₀₋₂R_(3t)R_(4t), wherein R_(3t) and R_(4t) are H or        C₁₋₂alkyl;

    -   (iii) or R_(1e) and R_(1f) are linked such that, together with        the nitrogen atom to which they are attached, they form a mono-        or bicyclic-heterocyclic ring, which is optionally substituted        by one or more substituents selected from C₁₋₄alkyl,        C₁₋₄haloalkyl, C₃₋₆cycloalkyl, cyano, hydroxy, C₁₋₄alkoxy, halo,        C₁₋₄haloalkoxy, NR_(1i)R_(1j) or —S(O)₀₋₂R_(1i)R_(1j), wherein        R_(1i) and R_(1j) are H or C₁₋₄alkyl, and/or the mono- or        bicyclic hetereocyclic ring formed by R_(1e) and R_(1f) is        optionally spiro-fused to a C₃₋₆cycloalkyl or a heterocyclic        ring; which in turn is optionally substituted by one or more        substituents selected from C₁₋₄alkyl, C₁₋₄haloalkyl,        C₃₋₆cycloalkyl, cyano, hydroxy, C₁₋₄alkoxy, halo,        C₁₋₄haloalkoxy, NR_(1i)R_(1j) or —S(O)O₂R_(1i)R_(1j), wherein        R_(1i) and R_(1j) are H or C₁₋₄alkyl;

    -   wherein any wherein any alkyl, alkoxy or C₃₋₆cycloalkyl is        further optionally substituted by one or more substituents        selected from cyano, hydroxy, halo, NR_(1k)R_(1l) or        —S(O)₀₋₂R_(1k)R_(1l), wherein R_(1k) and R_(1l) are H or        C₁₋₄alkyl.        10. A compound according to any preceding paragraph, or a or a        pharmaceutically acceptable salt thereof, wherein R_(1a) is a        group of the formula:

—(CR_(1c)R_(1d))_(p)—NR_(1e)R_(1f)

whereinp is an integer selected from 1 or 2;R_(1c) and R_(1d) are independently selected from:

-   -   (i) hydrogen (including deuterium),    -   (ii) C₁₋₃alkyl which is optionally substituted by one more        substituents selected from cyano, oxo, hydroxy, C₁₋₃alkoxy,        halo, C₁₋₃haloalkoxy, —O—C₃₋₄cycloalkyl, or NH₂; wherein        —O—C₃₋₆cycloalkyl is optionally substituted with halo, cyano or        hydroxy,    -   (iii) or R_(1c) and R_(1d) are linked together such that,        together with the carbon atom to which they are attached, they        form a 3- to 5-membered cycloalkyl or heterocyclic ring, or a        spirocyclic ring system, each of which is optionally substituted        by one or more substituents selected from C₁₋₂alkyl,        C₁₋₂haloalkyl, cyano, hydroxy, C₁₋₂alkoxy, halo or        C₁₋₂haloalkoxy;        R_(1e) is selected from:    -   (i) hydrogen (including deuterium);    -   (ii) C₁₋₃alkyl which is optionally substituted by one more        substituents selected from cyano, oxo, hydroxy, C₁₋₂alkoxy,        halo, C₁₋₂haloalkoxy and NH₂;        R_(1f) is a group with the formula:

—(CR_(1g)R_(1h))_(q)-T₁

-   -   wherein:    -   q is 1, 2 or 3;    -   R_(1g) and R_(1h) are independently selected from:    -   a) hydrogen (including deuterium); or    -   b) C₁₋₃alkyl which is optionally substituted by one more        substituents selected from cyano, oxo, hydroxy, C₁₋₄ alkoxy,        halo, C₁₋₄haloalkoxy, —O—C₃₋₆cycloalkyl, wherein        —O—C₃₋₆cycloalkyl is optionally substituted with halo, cyano or        hydroxy;    -   c) or R_(1g) and R_(1h) are optionally linked together such        that, together with the carbon atom to which they are attached,        they form a 3- to 4-membered cycloalkyl or heterocyclic ring        which is optionally substituted by one or more substituents        selected from C₁₋₂alkyl, C₁₋₂-haloalkyl, cyano, hydroxy,        C₁₋₂alkoxy, halo or C₁₋₂-haloalkoxy;    -   and T₁ is selected from halo, C₁₋₄alkyl, C₁₋₄haloalkyl, cyano,        hydroxy, NR_(1t)R_(2t) or —S(O)₀₋₂R_(1t)R_(2t) (wherein R_(1t)        and R_(2t) are H or C₁₋₄alkyl), C₃₋₈ cycloalkyl, C₂₋₃alkenyl,        C₂₋₃alkynyl, aryl, heterocyclyl, a mono- or bicyclic heteroaryl,        a spirocyclic carbocyclic or heterocyclic ring system, a bridged        C₃₋₈cycloalkyl, a bridged bicyclic C₅₋₁₂cycloalkyl, or a bridged        heterocyclic ring system, each of which is optionally        substituted by one or more substituents selected from C₁₋₂alkyl,        C₁₋₂-haloalkyl, cyano, hydroxy, C₁₋₂alkoxy, halo,        C₁₋₂haloalkoxy, C₃₋₆cycloalkyl, NR_(3t)R_(4t) or        —S(O)₀₋₂R_(3t)R_(4t), wherein R_(3t) and R_(4t) are H or        C₁₋₂alkyl;    -   or R_(1e) and R_(1f) are linked such that, together with the        nitrogen atom to which they are attached, they form a mono- or        bicyclic-heterocyclic ring, which is optionally substituted by        one or more substituents selected from C₁₋₄alkyl, C₁₋₄haloalkyl,        C₃₋₆cycloalkyl, cyano, hydroxy, C₁₋₄alkoxy, halo,        C₁₋₄haloalkoxy, NR_(1i)R_(1j) or —S(O)₀₋₂R_(1i)R_(1j), wherein        R_(1i) and R_(1j) are H or C₁₋₄alkyl, and/or the mono- or        bicyclic hetereocyclic ring formed by R_(1e) and R_(1f) is        optionally spiro-fused to a C₃₋₆cycloalkyl or a heterocyclic        ring, which in turn is optionally substituted by one or more        substituents selected from C₁₋₄alkyl, C₁₋₄haloalkyl,        C₃₋₆cycloalkyl, cyano, hydroxy, C₁₋₄alkoxy, halo,        C₁₋₄haloalkoxy, NR_(1i)R_(1j) or —S(O)₀₋₂R_(1i)R_(1j), wherein        R₁ and R, are H or C₁₋₄alkyl;        wherein any wherein any alkyl, alkoxy or C₃₋₆cycloalkyl is        further optionally substituted by one or more substituents        selected from cyano, hydroxy, halo, NR_(1k)R_(1l) or        —S(O)₀₋₂R_(1k)R_(1l), wherein R_(1k) and R_(1l) are H or        C₁₋₄alkyl.        11. A compound according to any preceding paragraph, or a        pharmaceutically acceptable salt thereof, wherein R_(1a) is a        group of the formula:

—(CR_(1c)R_(1d))_(p)—NR_(1e)R_(1f)

wherein

-   -   p is an integer selected from 1 or 2;        R_(1c) and R_(1d) are independently selected from:    -   (i) hydrogen (including deuterium),    -   (ii) C₁₋₃alkyl which is optionally substituted by one more        substituents selected from cyano, oxo, hydroxy, C₁₋₃alkoxy,        halo, C₁₋₃haloalkoxy, —O—C₃₋₄cycloalkyl, or NH₂; wherein        —O—C₃₋₆cycloalkyl is optionally substituted with halo, cyano or        hydroxy,    -   (iii) or R_(1c) and R_(1d) are linked together such that,        together with the carbon atom to which they are attached, they        form a 3- to 5-membered cycloalkyl or heterocyclic ring, or a        spirocyclic ring system, each of which is optionally substituted        by one or more substituents selected from C₁₋₂alkyl,        C₁₋₂haloalkyl, cyano, hydroxy, C₁₋₂alkoxy, halo or        C₁₋₂haloalkoxy;        R_(1e) is selected from:    -   (i) hydrogen (including deuterium);    -   (ii) C₁₋₃alkyl which is optionally substituted by one more        substituents selected from cyano, oxo, hydroxy, C₁₋₂alkoxy,        halo, C₁₋₂haloalkoxy and NH₂;        R_(1f) is a group with the formula:

—(CR_(1g)R_(1h))_(q)-T₁

-   -   wherein:    -   q is 1 or 2;    -   R_(1g) and R_(1h) are independently selected from:    -   a) hydrogen (including deuterium); or    -   b) C₁₋₃alkyl, which is optionally substituted by one more        substituents selected from cyano, oxo, hydroxy, C₁₋₂alkoxy,        halo, C₁₋₂haloalkoxy, —O—C₃cycloalkyl, wherein —O—C₃cycloalkyl        is optionally substituted with halo, cyano or hydroxy;    -   and T₁ is selected from C₁₋₄alkyl, C₃₋₆cycloalkyl, aryl,        heterocyclyl, heteroaryl, a spirocyclic carbocyclic or        heterocyclic ring system, a bridged C₃₋₈cycloalkyl, a bridged        bicyclic C₅₋₁₂cycloalkyl, or a bridged heterocyclic ring system,        each of which is optionally substituted by one or more        substituents selected from C₁₋₂alkyl, C₁₋₂haloalkyl, cyano,        hydroxy, C₁₋₂alkoxy, halo, C₁₋₂haloalkoxy or C₃₋₆cycloalkyl;    -   or R_(1e) and R_(1f) are linked such that, together with the        nitrogen atom to which they are attached, they form a mono- or        bicyclic-heterocyclic ring, which is optionally substituted by        one or more substituents selected from C₁₋₂alkyl, C₁₋₂haloalkyl,        C₃₋₆cycloalkyl, cyano, hydroxy, C₁₋₂alkoxy, halo,        C₁₋₂haloalkoxy, NR_(1i)R_(1j) or —S(O)₀₋₂R_(1i)R_(1j), wherein        R_(1i) and R_(1j) are H or C₁₋₂alkyl, and/or the mono- or        bicyclic hetereocyclic ring formed by R_(1e) and R_(1f) is        optionally spiro-fused to a C₃₋₆cycloalkyl or a heterocyclic        ring, which in turn is optionally substituted by one or more        substituents selected from C₁₋₂alkyl, C₃₋₆cycloalkyl, cyano,        hydroxy, C₁₋₂alkoxy, halo, C₁₋₂haloalkoxy, NR_(1i)R_(1j) or        —S(O)₀₋₂R_(1i)R_(1j), wherein R_(1i) and R_(1j) are H or        C₁₋₂alkyl;    -   wherein any wherein any alkyl, alkoxy or C₃₋₆cycloalkyl is        further optionally substituted by one or more substituents        selected from cyano, hydroxy, halo, NR_(1k)R_(1l) or        —S(O)₀₋₂R_(1k)R_(1l), wherein R_(1k) and R_(1l) are H or        C₁₋₄alkyl.        12. A compound according to any preceding paragraph, or a        pharmaceutically acceptable salt thereof, wherein R_(1a) is a        group of the formula:

—(CR_(1c)R_(1d))_(p)—NR_(1e)R_(1f)

-   -   p is an integer selected from 1 or 2;        R_(1c) and R_(1d) are independently selected from:    -   (i) hydrogen (including deuterium) or    -   (ii) C₁₋₃alkyl which is optionally substituted by one more        substituents selected from cyano, oxo, hydroxy, C₁₋₂alkoxy,        halo, C₁₋₂haloalkoxy, —O—C₃cycloalkyl;        R_(1e) is selected from hydrogen (including deuterium) or        C₁₋₂alkyl; and        R_(1f) is a group with the formula:

—(CR_(1g)R_(1h))_(q)-T₁

-   -   wherein:    -   q is 1 or 2;    -   R_(1g) and R_(1h) are independently selected from:    -   a) hydrogen (including deuterium); or    -   b) C₁₋₂alkyl, which is optionally substituted by one more        substituents selected from cyano, oxo, hydroxy, C₁₋₂ alkoxy,        halo or C₁₋₂haloalkoxy;    -   and T₁ is selected from C₁₋₄alkyl, C₃₋₆cycloalkyl, aryl,        heterocyclyl, a mono- or bicyclic heteroaryl, a spirocyclic        carbocyclic or heterocyclic ring system, a bridged        C₃₋₆cycloalkyl, a bridged bicyclic C₅₋₁₂cycloalkyl, or a bridged        heterocyclic ring system, each of which is optionally        substituted by one or more substituents selected from C₁₋₂alkyl,        C₁₋₂-haloalkyl, cyano, hydroxy, C₁₋₂alkoxy, halo, C₁₋₂haloalkoxy        or C₃₋₆cycloalkyl;        or R_(1e) and R_(1f) are linked such that, together with the        nitrogen atom to which they are attached, they form a mono- or        bicyclic-heterocyclic ring, which is optionally substituted by        one or more substituents selected from C₁₋₂alkyl, C₁₋₂haloalkyl,        C₃₋₆cycloalkyl, cyano, hydroxy, C₁₋₂alkoxy, halo or        C₁₋₂haloalkoxy, and/or the mono- or bicyclic hetereocyclic ring        formed by R_(1e) and R_(1f) is optionally spiro-fused to a        C₃₋₆cycloalkyl or a heterocyclic ring, which in turn is        optionally substituted by one or more substituents selected from        C₁₋₂alkyl, C₁₋₂-haloalkyl, C₃₋₆cycloalkyl, cyano, hydroxy,        C₁₋₂alkoxy, halo or C₁₋₂haloalkoxy; wherein any wherein any        alkyl, alkoxy or C₃₋₆cycloalkyl is further optionally        substituted by one or more substituents selected from cyano,        hydroxy, halo, NR_(1k)R_(1l) or —S(O)₀₋₂R_(1k)R_(1l), wherein        R_(1k) and R_(1l) are H or C₁₋₄alkyl.        13. A compound according to any preceding paragraph, or a        pharmaceutically acceptable salt thereof, wherein R_(1a) is a        group of the formula:

—(CR_(1c)R_(1a))_(p)—NR_(1e)R_(1f)

wherein

-   -   p is an integer selected from 1 or 2; R_(1c) and R_(1d) are        independently selected from hydrogen (including deuterium) or        C₁₋₂alkyl;    -   R_(1e) is selected from hydrogen (including deuterium) or        C₁₋₂alkyl; and    -   R_(1f) is a group with the formula:

—(CR_(1g)R_(1h))_(q)-T₁

-   -   -   wherein:        -   q is 1 or 2;

    -   R_(1g) and R_(1h) are independently selected from hydrogen        (including deuterium) or C₁₋₂alkyl;

    -   and T₁ is selected from C₁₋₄alkyl, C₃₋₄cycloalkyl, heterocyclyl,        a mono- or bicyclic heteroaryl, a spirocyclic carbocyclic or        heterocyclic ring system, a bridged C₃₋₈cycloalkyl, a bridged        bicyclic C₅₋₁₂cycloalkyl, or a bridged heterocyclic ring system,        each of which is optionally substituted by one or more        substituents selected from C₁₋₂alkyl, C₁₋₂haloalkyl, cyano,        hydroxy, C₁₋₂alkoxy, halo, C₁₋₂haloalkoxy or C₃₋₆cycloalkyl;

    -   or R_(1e) and R_(1f) are linked such that, together with the        nitrogen atom to which they are attached, they form a mono- or        bicyclic-heterocyclic ring, which is optionally substituted by        one or more substituents selected from C₁₋₂alkyl, C₁₋₂haloalkyl,        C₃₋₆cycloalkyl, cyano, hydroxy, C₁₋₂alkoxy, halo or        C₁₋₂haloalkoxy, and/or the mono- or bicyclic hetereocyclic ring        formed by R_(1e) and R_(1f) is optionally spiro-fused to a C₃₋₆        cycloalkyl or a heterocyclic ring, which in turn is optionally        substituted by one or more substituents selected from C₁₋₂alkyl,        C₁₋₂haloalkyl, C₃₋₆cycloalkyl, cyano, hydroxy, C₁₋₂alkoxy, halo        or C₁₋₂haloalkoxy; wherein any alkyl, alkoxy or C₃₋₆cycloalkyl        is further optionally substituted by one or more substituents        selected from cyano, hydroxy, halo, NR_(1k)R_(1l) or        —S(O)₀₋₂R_(1k)R_(1I), wherein R_(1k) and R_(1l) are H or        C₁₋₄alkyl.        14. A compound according to any preceding paragraph, or a        pharmaceutically acceptable salt thereof, wherein R_(1a) is a        group of the formula:

—(CR_(1c)R_(1d))_(p)—NR_(1e)R_(1f)

whereinp is 1;

-   -   R_(1c) and R_(1d) are independently selected from hydrogen        (including deuterium) or C₁₋₂alkyl;    -   R_(1e) is selected from hydrogen (including deuterium) or        C₁₋₂alkyl; and    -   R_(1f) is a group with the formula:

—(CR_(1g)R_(1h))_(q)-T₁

-   -   -   wherein:        -   q is 1 or 2;

    -   R_(1g) and R_(1h) are independently selected from hydrogen        (including deuterium) or C₁₋₂alkyl;

    -   and T₁ is selected from C₃₋₄cycloalkyl, heterocyclyl, a mono- or        bicyclic heteroaryl, a spirocyclic carbocyclic or heterocyclic        ring system, a bridged C₃₋₈cycloalkyl, a bridged bicyclic        C₅₋₁₂cycloalkyl, or a bridged heterocyclic ring system, each of        which is optionally substituted by one or more substituents        selected from C₁₋₂alkyl, C₁₋₂haloalkyl, cyano, hydroxy,        C₁₋₂alkoxy, halo, C₁₋₂-haloalkoxy or C₃₋₆cycloalkyl;        or R_(1e) and R_(1f) are linked such that, together with the        nitrogen atom to which they are attached, they form a mono- or        bicyclic-heterocyclic ring, which is optionally substituted by        one or more substituents selected from C₁₋₂alkyl, C₁₋₂haloalkyl,        C₃₋₆cycloalkyl, cyano, hydroxy, C₁₋₂alkoxy, halo or        C₁₋₂haloalkoxy, and/or the mono- or bicyclic hetereocyclic ring        formed by R_(1e) and R_(1f) is optionally spiro-fused to a        C₃₋₆cycloalkyl or a heterocyclic ring; which in turn is        optionally substituted by one or more substituents selected from        C₁₋₂alkyl, C₁₋₂-haloalkyl, C₃₋₆cycloalkyl, cyano, hydroxy,        C₁₋₂alkoxy, halo or C₁₋₂haloalkoxy, wherein any alkyl, alkoxy or        C₃₋₆cycloalkyl is further optionally substituted by one or more        substituents selected from cyano, hydroxy, halo, NR_(1k)R_(1l)        or —S(O)₀₋₂R_(1k)R_(1l), wherein R_(1k) and R_(1l) are H or        C₁₋₄alkyl.        15. A compound according to any preceding paragraph, or a        pharmaceutically acceptable salt thereof, wherein R_(1a) is a        group of the formula:

—(CR_(1c)R_(1d))_(p)—NR_(1e)R_(1f)

wherein

-   -   R_(1c) and R_(1d) are independently selected from hydrogen        (including deuterium) or C₁₋₂alkyl;    -   R_(1e) is selected from hydrogen (including deuterium) or        C₁₋₂alkyl; and    -   R_(1f) is a group with the formula:

—(CR_(1g)R_(1h))_(q)-T₁

-   -   -   wherein:        -   q is 1;

    -   R_(1g) and R_(1h) are independently selected from hydrogen        (including deuterium) or C₁₋₂alkyl;        -   and T₁ is selected from C₃₋₄cycloalkyl, heterocyclyl, a            spirocyclic carbocyclic or heterocyclic ring system, a            bridged C₃₋₈cycloalkyl, a bridged bicyclic C₅₋₁₂cycloalkyl,            or a bridged heterocyclic ring system, each of which is            optionally substituted by one or more substituents selected            from C₁₋₂alkyl, C₁₋₂haloalkyl, cyano, hydroxy, C₁₋₂alkoxy,            halo, C₁₋₂haloalkoxy or C₃₋₆cycloalkyl,        -   wherein any alkyl or alkoxy is optionally further            substituted by one or more substituents selected from cyano,            hydroxy or halo.            16. A compound according to any preceding paragraph, or a or            a pharmaceutically acceptable salt thereof, wherein R_(1a)            is a group of the formula:

—(CR_(1c)R_(1d))_(p)—NR_(1e)R_(1f)

wherein

-   -   p is 1;        -   R_(1c) and R_(1d) are independently selected from hydrogen            (including deuterium) or C₁₋₂alkyl; and            -   R_(1e) and R_(1f) are linked such that, together with                the nitrogen atom to which they are attached, they form                a mono- or bicyclic-heterocyclic ring, which is                optionally substituted by one or more substituents                selected from C₁₋₂alkyl, C₁₋₂haloalkyl, C₃₋₆cycloalkyl,                cyano, hydroxy, C₁₋₂alkoxy, halo or C₁₋₂haloalkoxy,                and/or the mono- or bicyclic hetereocyclic ring formed                by R_(1e) and R_(1f) is optionally spiro-fused to a                C₃₋₆cycloalkyl or a heterocyclic ring, which in turn is                optionally substituted by one or more substituents                selected from C₁₋₂alkyl, C₁₋₂haloalkyl, cyano, hydroxy,                C₁₋₂alkoxy, halo or C₁₋₂haloalkoxy.                17. A compound according to any preceding paragraph, or                a or a pharmaceutically acceptable salt thereof, wherein                R_(1a) is

-   -   wherein T₁ is as defined in any of paragraphs 1 to 16.        18. A compound according to any preceding paragraph, wherein        R_(1a) is selected from methoxy;

19. A compound according to any preceding paragraph, or a or apharmaceutically acceptable salt thereof, wherein R_(1a) is selectedfrom:

20. A compound according to any preceding paragraph, or a or apharmaceutically acceptable salt thereof, wherein R_(1a) is selectedfrom:

21. A compound according to any preceding paragraph, or a or apharmaceutically acceptable salt thereof, or a or a pharmaceuticallyacceptable salt thereof, wherein R_(1a) is selected from:methoxy;

22. A compound according to any preceding paragraph, or apharmaceutically acceptable salt thereof, wherein R_(1b) is selectedfrom hydrogen, halo or C₁₋₂ alkyl.23. A compound according to any preceding paragraph, or apharmaceutically acceptable salt thereof, wherein R_(2a), R_(2b), R_(2c)and R_(2d) are independently selected from hydrogen, cyano, halo or agroup of the formula:

-L_(2a)-L_(2b)-Q₂

whereinL_(2a) is absent or C₁₋₃alkylene optionally substituted by C₁₋₂ alkyl oroxo;L_(2b) is absent or selected from O, S, N(R_(n)), C(O), C(O)O, OC(O),C(O)N(R_(n)), N(R_(n))C(O),N(R_(n))C(O)N(R_(o)), wherein R_(n) and R_(o) are each independentlyselected from hydrogen or C₁₋₂ alkyl; andQ₂ is hydrogen, cyano, C₁₋₆alkyl, C₃₋₆cycloalkyl, aryl, heterocyclyl orheteroaryl, each of which is optionally substituted by one or moresubstituents selected from halo, trifluoromethyl, trifluoromethoxy,amino, cyano, hydroxy, amino, carboxy, carbamoyl, sulphamoyl, C₁₋₄alkyl,NR_(p)R_(q), OR_(p), C(O)R_(p), wherein R_(p) and R_(q) are eachindependently selected from hydrogen or C₁₋₄alkyl.24. A compound according to any preceding paragraph, or apharmaceutically acceptable salt thereof, wherein R_(2a), R_(2b), R_(2c)and R_(2d) are independently selected from hydrogen, cyano, halo or agroup of the formula:

-L_(2a)-L_(2b)-Q₂

whereinL_(2a) is absent or C₁₋₃alkylene optionally substituted by C₁₋₂ alkyl;L_(2b) is absent or selected from O, S, N(R_(n)), C(O); andQ₂ is hydrogen, cyano, C₁₋₆alkyl, C₃₋₆cycloalkyl, aryl, heterocyclyl orheteroaryl, each of which is optionally substituted by one or moresubstituents selected from halo, trifluoromethyl, trifluoromethoxy,amino, cyano and hydroxy.25. A compound according to any preceding paragraph, or apharmaceutically acceptable salt thereof, wherein R_(2a), R_(2b), R_(2c)and R_(2d) are independently selected from hydrogen, cyano, C₁₋₆ alkoxy,C₁₋₆ haloalkoxy, halo, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₆cycloalkyl, aryl,heterocyclyl or heteroaryl, each of which is optionally substituted byone or more substituents selected from halo, trifluoromethyl,trifluoromethoxy, amino, cyano and hydroxy.26. A compound according to any preceding paragraph, or apharmaceutically acceptable salt thereof, wherein R_(2a), R_(2b), R_(2c)and R_(2d) are independently selected from hydrogen, cyano, halo orC₁₋₃alkyl.27. A compound according to any preceding paragraph, or apharmaceutically acceptable salt thereof, wherein R_(2a), R_(2b), R_(2c)and R_(2d) are hydrogen.28. A compound according to any preceding paragraph, or apharmaceutically acceptable salt thereof, wherein R_(3a1), R_(3b1),R_(3c1), R_(3d1), R_(3e1), R_(3f1), R_(3g1), R_(3h1), R_(3i1), R_(3j1),R_(3k1), R_(3l1), R_(3m1), R_(3n1), R_(3o1), R_(3p1), R_(3q1), R_(3r1)and R_(3s1) are independently selected from hydrogen (includingdeuterium), C₁₋₆alkyl; wherein C₁₋₆alkyl is optionally substituted withone or more substituents selected from halo, amino, cyano, and hydroxy.29. A compound according to any one of the preceding paragraphs, or apharmaceutically acceptable salt thereof, wherein R_(3a2), R_(3b2),R_(3c2), R_(3d2), R_(3e2), R_(3f2), R_(3g2), R_(3h2), R_(3i2), R_(3j2),R_(3k2), R_(3l2), R_(3m2), R_(3n2), R_(3o2), R_(3p2), R_(3q2), R_(3r2)and R_(3s2) are hydrogen.30. A compound according to any one of the preceding paragraphs, or apharmaceutically acceptable salt thereof, wherein n is 1.31. A compound according to any one of the preceding paragraphs, or apharmaceutically acceptable salt thereof, wherein Y is selected from:

wherein n, R_(3a1), R_(3a2), R_(3b1), R_(3b2), R_(3e1), R_(3e2),R_(3i1), R_(3i2), R_(3j1) and R_(3j2) are as defined in any precedingparagraph.32. A compound according to any one of the preceding paragraphs, or apharmaceutically acceptable salt thereof, wherein Y is selected from:

33. A compound according to any one of the preceding paragraphs, or apharmaceutically acceptable salt thereof, wherein Y is selected from

34. A compound according to any one of the preceding paragraphs, or apharmaceutically acceptable salt thereof, wherein Z is selected from:

-   -   wherein:    -   R₄ is selected from hydrogen, halo, cyano and methyl;    -   R₅ is selected from hydrogen, halo, cyano and methyl;    -   R₆ is selected from hydrogen, halo, cyano and methyl;    -   R₈, R₉, R₁₀ and R₁₁ are independently selected from hydrogen,        NH₂, halo, cyano, and C₁₋₆ alkyl; or    -   R₉ and R₁₀ may be linked together such that, together to the        atoms to which they are attached, they form a fused 5- or        6-membered saturated or unsaturated ring system, or R₁₀ and R₁₁        may be linked together such that, together to the atoms to which        they are attached, they form a fused 5- or 6-membered saturated        or unsaturated ring system, wherein either of the fused 5- or        6-membered saturated or unsaturated ring system may be        optionally substituted by one or more substituents selected from        C₁₋₂alkyl, cyano, C₁₋₂haloalkyl, hydroxy, C₁₋₂alkoxy, halo,        C₁₋₂haloalkoxy, NR_(1ia)R_(1ia) or —S(O)₀₋₂R_(1ia)R_(1ia),        wherein R_(1ia) and R_(1ja) are H or C₁₋₂alky;    -   R₇ and R_(11N) are independently selected from hydrogen, NH₂,        halo, cyano, and C₁₋₆ alkyl;    -   R_(Z1) and R_(Z1a) are selected from hydrogen, C₁₋₄alkyl, cyano,        halo, C₁₋₄haloalkyl, C₁₋₄haloalkoxy, C₁₋₄alkoxy, C₃₋₆cycloalkyl        and —O—C₃₋₆cycloalkyl, wherein C₃₋₆cycloalkyl and        —O—C₃₋₆cycloalkyl are optionally substituted by one or more of        halo, methyl or methoxy;    -   R_(Z2) and R_(Z2a) are selected from hydrogen, C₁₋₄alkyl, cyano,        halo, NH₂ and C₁₋₄alkoxy;    -   R_(Z3a) is selected from hydrogen, C₁₋₄alkyl, cyano, halo, NH₂        and C₁₋₄alkoxy;    -   R_(Zi1b) is selected from hydrogen, C₁₋₄alkyl, cyano, halo, NH₂        and C₁₋₄alkoxy;    -   R_(Zi2e) is selected from hydrogen, C₁₋₄alkyl, cyano, halo, NH₂        and C₁₋₄alkoxy;    -   R_(Z9) is selected from hydrogen, halo, cyano, C₁₋₄ alkyl, C₁₋₄        haloalkyl, C₁₋₄alkoxy, C₁₋₄ haloalkoxy;    -   R_(Z10) is independently selected from hydrogen, halo, cyano,        C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄alkoxy, C₁₋₄ haloalkoxy;    -   R_(Z11) is selected from hydrogen, halo, cyano, C₁₋₄ alkyl, C₁₋₄        haloalkyl, C₁₋₄alkoxy, C₁₋₄ haloalkoxy;    -   R_(Z12) is independently selected from hydrogen, halo, cyano,        C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄alkoxy, C₁₋₄ haloalkoxy;    -   R_(Z13) is independently selected from hydrogen, halo, cyano,        C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄alkoxy, C₁₋₄ haloalkoxy;    -   R_(Z14) is selected from hydrogen, halo, cyano, C₁₋₄ alkyl, C₁₋₄        haloalkyl, C₁₋₄alkoxy, C₁₋₄ haloalkoxy;    -   R_(Z15) is independently selected from hydrogen, halo, cyano,        C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄alkoxy, C₁₋₄ haloalkoxy;    -   R_(Z16) is independently selected from hydrogen, halo, cyano,        C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄alkoxy, C₁₋₄ haloalkoxy;    -   A₁ is selected from CR₁₂ and N;    -   A₂ is selected from CR₁₃ and N;    -   A₅ is selected from CR₁₆ and N;    -   A₆ is selected from CR₁₇ and N;    -   A₇ is selected from CR₁₆ and N;    -   A₈ is selected from CR₁₉R₂₀ and NR₂₁;    -   A₉ is selected from CR₂₂R₂₃ and NR₂₄;    -   A₁₁ is selected from CR₂₈R₂₉ and NR₃₀;    -   R₁₂ is selected from hydrogen, halo, cyano, C₁₋₄ alkyl, C₁₋₄        haloalkyl, C₁₋₄alkoxy, C₁₋₄ haloalkoxy (e.g. hydrogen, halo,        cyano and C₁₋₄ alkyl);    -   R₁₃ is selected from hydrogen, halo, cyano, C₁₋₄ alkyl, C₁₋₄        haloalkyl, C₁₋₄alkoxy, C₁₋₄ haloalkoxy (e.g. hydrogen, halo,        cyano, methoxy and methyl);    -   R₁₆ and R₁₈ are selected from hydrogen, halo, cyano, C₁₋₄ alkyl,        C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄haloalkoxy, C₃₋₄cycloalkyl, a        3- to 4-membered heterocyclyl and C₃₋₄ cycloalkoxy;    -   R₁₇ is selected from hydrogen, halo, cyano, C₁₋₄ alkyl, C₁₋₄        haloalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, C₂₋₄ alkenyl, C₂₋₄        alkynyl, phenyl, a 5- or 6-membered or heteroaryl,        C₃₋₆cycloalkyl, —O—C₃₋₆cycloalkyl, heterocyclyl, —O-heterocyclyl        (carbon-linked), —(OCH₂CH₂)_(m)—OCH₃ wherein m is an integer        from 1 to 6, NR_(q)R_(r), wherein R_(q) and R_(r) are each        independently hydrogen, C₁₋₅ alkyl, C₃₋₆cycloalkyl, a 3- to        6-membered carbon-linked heterocyclyl, or R_(q) and R_(r) are        linked together such that, together with the nitrogen atom to        which they are attached, they form a 3- to 6-membered        heterocyclic ring; wherein any C₁₋₅alkyl, C₁₋₄ alkoxy,        C₂₋₄alkenyl, C₂₋₄alkynyl, phenyl, 5- or 6-membered or        heteroaryl, C₃₋₆cycloalkyl, —O—C₃₋₆cycloalkyl, heterocyclyl or        —O— heterocyclyl (carbon-linked) is optionally further        substituted by one or more substituents selected from C₁₋₂alkyl,        cyano, C₁₋₂haloalkyl, hydroxy, C₁₋₂alkoxy, halo, C₁₋₂haloalkoxy,        NR_(1ea)R_(1fa) or —S(O)₀₋₂R_(1ea)R_(1fa), wherein R_(1ea) and        R_(1fa) are H or C₁₋₂alkyl;    -   R₁₉ and R₂₀ are selected from hydrogen, halo, cyano and C₁₋₄        alkyl;    -   R₂₂ and R₂₃ are selected from selected from hydrogen, halo,        cyano, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄alkoxy, C₁₋₄ haloalkoxy        (e.g. hydrogen, halo, cyano and methyl);    -   R₂₈ and R₂₉ are selected from hydrogen, halo, methoxy and        methyl;    -   R₂₁, R₂₄ and R₃₀ are hydrogen or C₁₋₄alkyl.        34. A compound according to any preceding paragraph, or a        pharmaceutically acceptable salt thereof, wherein:    -   (i) R₄, R₅, R_(X5a), R_(X5b), R_(Y5), R₆, R₇, R₈, R₉, R₁₀, R₁₁,        R_(11a), R_(11b), R_(Z2), R_(Z2a), R_(Z3a), R_(Zi1b), R_(Zi2e),        R_(Z9), R_(Z10), R_(Z11), R_(Z12), R_(Z12a), R_(Z13), R_(Z14),        R_(Z15) and R_(Z16) are independently selected from hydrogen,        methyl, cyano or halo; and    -   R_(B5N), R_(Y5N), and R_(11N) are selected from methyl or        hydrogen;    -   (ii) R_(Z1) and R_(Z1a) are selected from hydrogen, C₁₋₄alkyl,        cyano, halo, C₁₋₄haloalkyl, C₁₋₄haloalkoxy, C₁₋₄alkoxy,        C₃₋₆cycloalkyl and —O—C₃₋₆cycloalkyl;    -   (iii) R₁₂, R₁₃, R₁₆, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, R₂₃, R₂₄ and R₃₀        are independently selected from hydrogen, halo, cyano and        methyl;    -   (iv) R₁₇ is selected from hydrogen, halo, cyano, C₁₋₄ alkyl,        C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, C₂₋₄ alkenyl, C₂₋₄        alkynyl, phenyl a 5- or 6-membered or heteroaryl,        C₃₋₆cycloalkyl, —O—C₃₋₆cycloalkyl, heterocyclyl,        —(OCH₂CH₂)_(m)—OCH₃ wherein m is an integer from 1 to 6,        NR_(q)R_(r), wherein R_(q) and R_(r) are each independently        hydrogen, C₁₋₄ alkyl or R_(q) and R_(r) are linked together such        that, together with the nitrogen atom to which they are        attached, they form a 3- to 6-membered heterocyclic ring;        wherein any C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, phenyl, 5-        or 6-membered or heteroaryl, C₃₋₆cycloalkyl, —O—C₃₋₆cycloalkyl,        heterocyclyl or —O-heterocyclyl (carbon-linked) is optionally        further substituted by one or more substituents selected from        C₁₋₂alkyl, cyano, C₁₋₂haloalkyl, hydroxy, C₁₋₂ alkoxy, halo,        C₁₋₂haloalkoxy, NR_(1ea)R_(1fa) or —S(O)₀₋₂R_(1ea)R_(1fa),        wherein R_(1ea) and R_(1fa) are H or C₁₋₂alkyl.    -   (v) R₂₁, R₂₄ and R₃₀, are independently selected from hydrogen        or methyl;    -   (vi) R₂₈ and R₂₉ are selected from hydrogen or halo, methoxy and        methyl.        35. A compound according to any preceding paragraph, or a        pharmaceutically acceptable salt thereof, wherein:    -   (i) R₄, R₅, R_(X5a), R_(X5b), R_(Y5), R_(B5N), R_(Y5N), R₆, R₇,        R₈, R₉, R₁₀, R₁₁, R_(11a), R_(11b), R_(11N), R_(Z2), R_(Z2a),        R_(Z3a), R_(Zi1b), R_(Zi2e), R_(Z9), R_(Z10), R_(Z11), R_(Z12),        R_(Z12a), R_(Z13), R_(Z14), R_(Z15) and R_(Z16) are hydrogen;    -   (ii) R_(Z1) and R_(Z1a) are selected from hydrogen, cyano, halo,        C₁₋₂haloalkyl, C₁₋₂haloalkoxy, C₁₋₂alkoxy, C₃₋₆cycloalkyl and        —O—C₃₋₆cycloalkyl;    -   (iii) R₁₂, R₁₃, R₁₆, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, R₂₃, R₂₄ and R₃₀        are hydrogen; (iv) R₁₇ is selected from hydrogen, halo, cyano,        C₁₋₂ alkyl, C₁₋₂ haloalkyl, C₁₋₂ alkoxy, C₁₋₂ haloalkoxy, C₂₋₃        alkenyl, C₂₋₃ alkynyl, phenyl a 5- or 6-membered or heteroaryl,        C₃₋₆ cycloalkyl, —O—C₃₋₆cycloalkyl, heterocyclyl,        —(OCH₂CH₂)_(m)—OCH₃ wherein m is an integer from 1 to 6,        NR_(q)R_(r), wherein R_(q) and R_(r) are each independently        hydrogen, C₁₋₂ alkyl or R_(q) and R_(r) are linked together such        that, together with the nitrogen atom to which they are        attached, they form a 3- to 6-membered heterocyclic ring;        wherein any C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, phenyl, 5-        or 6-membered or heteroaryl, C₃₋₆cycloalkyl, —O—C₃₋₆cycloalkyl,        heterocyclyl or —O-heterocyclyl (carbon-linked) is optionally        further substituted by one or more substituents selected from        C₁₋₂alkyl, cyano, C₁₋₂haloalkyl, hydroxy, C₁₋₂alkoxy, halo,        C₁₋₂haloalkoxy, NR_(1ea)R_(1fa) or —S(O)₀₋₂R_(1ea)R_(1fa),        wherein R_(1ea) and R_(1fa) are H or C₁₋₂alkyl    -   (v) R₂₁, R₂₄ and R₃₀, are hydrogen;    -   (vi) R₂₈ and R₂₉ are hydrogen.        36. A compound according to any one of the preceding paragraphs,        wherein    -   when X₆ is A₁, A₁ is CR₁₂;    -   when X₇ is A₂, A₂ is CR₁₃;    -   B₁ is A₅, wherein A₅ is CR₁₆;    -   B₂ is A₆, wherein A₆ is CR₁₇;    -   Y₂ is A₇, wherein is CR₁₈;    -   when X₆ is A₈, A₈ is CR₁₉R₂₀;    -   when X₇ is A₉, A₉ is CR₂₂R₂₃;    -   when X₇ is A₁₁, A₁₁ is CR₂₈R₂₉;        and wherein R₁₂, R₁₃, R₁₆, R₁₇, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, R₂₃,        R₂₈ and R₂₉ are as defined in any one of the preceding        paragraphs.        37. A compound according to any preceding paragraph, or a        pharmaceutically acceptable salt thereof, wherein R₁₇ is        selected from hydrogen, halo, cyano, C₁₋₂ alkyl, C₁₋₂ haloalkyl,        C₁₋₂ alkoxy, C₁₋₂ haloalkoxy, C₂₋₃ alkenyl, C₂₋₃ alkynyl, phenyl        a 5- or 6-membered or heteroaryl, C₃₋₆cycloalkyl,        —O—C₃₋₆cycloalkyl, heterocyclyl, —O-heterocyclyl        (carbon-linked), —(OCH₂CH₂)_(m)—OCH₃ wherein m is an integer        from 1 to 6, NR_(q)R_(r), wherein R_(q) and R_(r) are each        independently hydrogen, C₁₋₂ alkyl or R_(q) and R_(r) are linked        together such that, together with the nitrogen atom to which        they are attached, they form a 3- to 6-membered heterocyclic        ring;        wherein any C₁. alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, phenyl, 5- or        6-membered or heteroaryl, C₃₋₆cycloalkyl, —O—C₃₋₆cycloalkyl,        heterocyclyl or —O-heterocyclyl (carbon-linked) is optionally        further substituted by one or more substituents selected from        C₁₋₂alkyl, cyano, C₁₋₂haloalkyl, hydroxy, C₁₋₂alkoxy, halo,        C₁₋₂haloalkoxy, NR_(1ea)R_(1fa) or —S(O)₀₋₂R_(1ea)R_(1fa),        wherein R_(1ea) and R_(1fa) are H or C₁₋₂alkyl.        38. A compound according to any preceding paragraph, or a        pharmaceutically acceptable salt thereof, wherein R₁₇ is        selected from hydrogen, halo, cyano, C₁₋₄ alkyl, C₁₋₄ haloalkyl,        C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, C₂₋₄ alkenyl, C₂₋₄ alkynyl,        C₃₋₆cycloalkyl, —O—C₃₋₄cycloalkyl, heterocyclyl,        —(OCH₂CH₂)_(m)—OCH₃ wherein m is 1, 2 or 3, NR_(q)R_(r), wherein        R_(q) and R_(r) are each independently hydrogen or C₁₋₂ alkyl;        wherein any C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,        C₃₋₆cycloalkyl, —O—C₃₋₄cycloalkyl, heterocyclyl, system is        optionally further substituted by one or more substituents        selected from C₁₋₂alkyl, C₁₋₂haloalkyl, cyano, hydroxy,        C₁₋₂alkoxy, halo and C₁₋₂haloalkoxy.        39. A compound according to any one of the preceding paragraphs,        or a pharmaceutically acceptable salt thereof, wherein R_(Z1)        and R_(Z1a) are selected from hydrogen, cyano or halo.        40. A compound according to any one of the preceding paragraphs,        or a pharmaceutically acceptable salt thereof, wherein Z is        selected from:

A₁, A₂, A₅, A₆, A₇, A₈, A₉, A₁₁, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁,R_(Y5N), R_(Z1), R_(Z2), R_(Z10), R_(Z12), R_(Z13), R_(Z14), R_(Z15),R_(Z16), R_(Z2a), R_(Z3a), R_(Z1a), R_(Zi1b) and R_(Zi2e) are as definedin any one of the preceding paragraphs.41. A compound according to any one of the preceding paragraphs, or apharmaceutically acceptable salt thereof, wherein Z is selected from:

wherein A₁, A₂, A₅, A₆, A₇, A₈, A₉, A₁₁, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀,R₁₁, R_(Y5N), R_(Z1), R_(Z2), R_(Z10), R_(Z12), R_(Z13), R_(Z14),R_(Z15), R_(Z16), R_(Z2a), R_(Z3a), R_(Z1a), R_(Zi1b) and R_(Zi2e) areas defined in any one of the preceding paragraphs.42. A compound according to any one of the preceding paragraphs, or apharmaceutically acceptable salt thereof, wherein Z is selected from:

wherein R₈, R₁₀, R₁₇, R₁₈ and R_(Z1), are as defined herein in any oneof the preceding paragraphs.43. A compound according to any one of the preceding paragraphs, or apharmaceutically acceptable salt thereof, wherein Z is selected from:

44. A compound according to paragraph 1, or a pharmaceuticallyacceptable salt thereof, wherein:

X is

Y is selected from:

and

Z is selected from:

wherein:

-   -   (i) R_(1a), R_(1b), R_(2a), R_(2b) and R_(2d) are as defined in        any preceding paragraph;    -   (ii) R_(3a1), R_(3a2), R_(3b1), R_(3b2), R_(3i1), R_(3i2),        R_(3j1), R_(3j2) and n are as defined in any preceding        paragraph; and    -   (iii) A₁, A₂, A₅, A₆, A₇, R₄, R₅, R₆, R_(Z1), R_(Z2), R_(Z10),        R_(Z12), R_(Z13), R_(Z14), R_(Z15), R_(Z16), R_(Z2a), R_(Z3a),        R_(Zi2e), R_(Zi1b) and R_(Z2) are as defined in any preceding        paragraph.        45. A compound according to paragraph 44, or a pharmaceutically        acceptable salt thereof, wherein:

X is

Y is

Z is

wherein:

-   -   (i) R_(1a), R_(1b), R_(2a), R_(2b) and R_(2d) are as defined in        any preceding paragraph;    -   (ii) n, R_(3a1), R_(3a2), R_(3j1), R_(3j2), are as defined in        any preceding paragraph; and    -   (iii) A₁, A₂, A₅, A₆, A₇, R₄, R₅, R₆, R₈, R₉, R₁₀, R₁₁, R_(Z1),        R_(Z2), R_(Z2a), R_(Z3a), R_(Zi2e), R_(Zi1b) are as defined in        any preceding paragraph.        46. A compound according to paragraph 44, or a pharmaceutically        acceptable salt thereof, wherein:

X is

Y is

and

Z is

(i) wherein R_(1a), R_(1b), R_(2a), R_(2b) and R_(2d) are as defined inany preceding paragraph;

(ii) n, R_(3a1) and R_(3a2) are as defined in any preceding paragraph;and

(iii) A₁, A₂, R₄, R₅ and R₆ are as defined in any preceding paragraph.

47. A compound, or a pharmaceutically acceptable salt thereof, selectedfrom any one of the following:

-   N-({2-[(4,4-dimethylpiperidin-1-yl)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[(2-{[(cyclobutylmethyl)amino]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[[2-[[(3,3-difluorocyclobutyl)methylamino]methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[[2-[[(1-hydroxycyclobutyl)methylamino]methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[[2-[[(1-fluorocyclobutyl)methylamino]methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[[2-[[(1-methylcyclopropyl)methylamino]methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide.-   N-[[2-(2-azabicyclo[2.1.1]hexan-2-ylmethyl)-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[[2-(3-azabicyclo[3.1.1]heptanean-3-ylmethyl)-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[[2-[[2-(hydroxymethyl)pyrrolidin-1-yl]methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[[2-(morpholinomethyl)-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[[2-[(1-adamantylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide-   4-oxo-N-[[2-(1-piperidylmethyl)-1H-indol-6-yl]methyl]pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[[2-[(4-fluoro-1-piperidyl)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide-   4-oxo-N-[[2-[[[rac-(1S,2S,4S)-7-oxabicyclo[2.2.1]heptane-5-en-2-yl]methylamino]methyl]-1H-indol-6-yl]methyl]pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[[2-[[(1-hydroxycyclopentyl)methylamino]methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide-   4-oxo-N-[[2-[[[rac-(1S,2R,4S)-7-oxabicyclo[2.2.1]heptane-5-en-2-yl]methylamino]methyl]-1H-indol-6-yl]methyl]pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[[2-[(1-bicyclo[1.1.1]pentanylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[[2-[(cyclobutylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-({2-[({bicyclo[2.2.1]heptanean-2-yl}amino)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[[2-[(cyclopropylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[[2-(2-azabicyclo[2.2.2]octan-2-ylmethyl)-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[[2-[[(2,2-difluorocyclopropyl)methylamino]methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[(2-{[({3-fluorobicyclo[1.1.1]pentan-1-yl}methyl)amino]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[[2-[(cyclohexylmethylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[[2-[[(1-hydroxycyclohexyl)methylamino]methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[[2-[(cyclopentylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[[2-[(cyclopentylmethylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[[2-[[(1-methoxycyclobutyl)methylamino]methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[[2-[(isobutylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[[2-[(cyclohexylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[[2-[(cyclopropylmethylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide-   4-oxo-N-[[2-[(prop-2-ynylamino)methyl]-1H-indol-6-yl]methyl]pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[[2-[(oxetan-2-ylmethylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[[2-[(2,2-dimethylpropylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[[2-[(1-bicyclo[1.1.1]pentanylmethylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-{[2-({[(1S,2S)-2-hydroxycyclopentyl]amino}methyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-{[2-({[(1R,2R)-2-hydroxycyclopentyl]amino}methyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-{[2-({[(1S,2R)-2-hydroxycyclopentyl]amino}methyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-{[2-({[(1R,2S)-2-hydroxycyclopentyl]amino}methyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[[2-[(cyclopropylmethylamino)methyl]-5-fluoro-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[[2-[(cyclobutylmethylamino)methyl]-5-fluoro-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide-   4-oxo-N-[[2-[(2,2,2-trifluoroethylamino)methyl]-1H-indol-6-yl]methyl]pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[(2-{[N-(cyclobutylmethyl)acetamido]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   4-oxo-N-{[2-(piperidin-2-yl)-1H-indol-6-yl]methyl}-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[(2-{[(cyclobutylmethyl)amino]methyl}-3-fluoro-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[(2-{[(cyclobutylmethyl)amino]methyl}-1-methyl-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[[2-[(Cyclobutylmethylamino)-dideuterio-methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[[2-[(cyclobutylmethylamino)methyl]-1H-indol-6-yl]methyl]-1H-indazole-4-carboxamide-   N-[[2-[(cyclobutylmethylamino)methyl]-1H-pyrrolo[3,2-b]pyridin-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-(1H-indol-6-ylmethyl)-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-(1H-indol-2-ylmethyl)-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-(indolizin-2-ylmethyl)-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[(6-{[4-(1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl]methyl}-1H-indol-2-yl)methyl]cyclopropanamine-   (1R,2S)-2-[[6-[[4-(1H-indazol-4-yl)triazol-1-yl]methyl]-1H-indol-2-yl]methylamino]cyclopentanol-   N-[[6-[[4-(1H-indazol-4-yl)triazol-1-yl]methyl]-1H-indol-2-yl]methyl]cyclopentanamine-   N-(cyclopropylmethyl)-1-[6-[[4-(1H-indazol-4-yl)triazol-1-yl]methyl]-1H-indol-2-yl]methanamine-   1-[[[6-[[4-(1H-indazol-4-yl)triazol-1-yl]methyl]-1H-indol-2-yl]methylamino]methyl]cyclobutanol-   N-(cyclobutylmethyl)-1-[6-[[4-(1H-indazol-4-yl)triazol-1-yl]methyl]-1H-indol-2-yl]methanamine-   N-(cyclobutylmethyl)-1-[6-[[4-(1H-indazol-4-yl)triazol-1-yl]methyl]-1H-pyrrolo[3,2-b]pyridin-2-yl]methanamine-   N-(cyclobutylmethyl)-1-[6-[[4-(1H-indazol-4-yl)triazol-1-yl]methyl]-1H-pyrrolo[3,2-c]pyridin-2-yl]methanamine-   N-(cyclobutylmethyl)-1-[6-[[4-(1H-indazol-4-yl)triazol-1-yl]methyl]-1H-pyrrolo[3,2-c]pyridin-2-yl]methanamine-   2-[1-[[2-[(cyclobutylmethylamino)methyl]-1H-indol-6-yl]methyl]triazol-4-yl]pyrido[1,2-a]pyrimidin-4-one-   N-(cyclobutylmethyl)-1-[6-[[4-(6-methoxyimidazo[1,5-a]pyridin-8-yl)triazol-1-yl]methyl]-1H-indol-2-yl]methanamine-   N-(cyclobutylmethyl)-1-[6-[[4-(1H-indazol-4-yl)imidazol-1-yl]methyl]-1H-indol-2-yl]methanamine-   N-(cyclobutylmethyl)-1-[6-[[3-(1H-indazol-4-yl)-1,2,4-oxadiazol-5-yl]methyl]-1H-indol-2-yl]methanamine-   N-[[2-(2-azaspiro[3.3]heptanean-2-ylmethyl)-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[[2-[(benzylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[[2-(3-azabicyclo[3.1.0]hexan-3-ylmethyl)-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[[2-[[cyclobutylmethyl(methyl)amino]methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[[2-[(cyclobutylmethylamino)methyl]-1H-pyrrolo[2,3-b]pyridin-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[(2-{[(cyclobutylmethyl)amino]methyl}-1H-1,3-benzodiazol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[(2-{[(but-2-yn-1-yl)amino]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[(2-{[(3-cyclopropylprop-2-yn-1-yl)amino]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-({2-[({bicyclo[3.1.0]hexan-6-yl}amino)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[(2-{[({bicyclo[2.1.1]hexan-1-yl}methyl)amino]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[(2-{[({3-methylbicyclo[1.1.1]pentan-1-yl}methyl)amino]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-({2-[(3-methylazetidin-1-yl)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-({2-[(3-fluoroazetidin-1-yl)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-({2-[(azetidin-1-yl)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-{[2-({2-azaspiro[3.4]octan-2-yl}methyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-({2-[(3-hydroxyazetidin-1-yl)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-({2-[(3,3-dimethylazetidin-1-yl)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   4-oxo-N-[(2-{[3-(2,2,2-trifluoroethoxy)azetidin-1-yl]methyl}-1H-indol-6-yl)methyl]-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[(2-{[3-(difluoromethyl)azetidin-1-yl]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-({2-[(3-methoxyazetidin-1-yl)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[(2-{[3-(tert-butoxy)azetidin-1-yl]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   4-oxo-N-[(2-{[3-(trifluoromethyl)azetidin-1-yl]methyl}-1H-indol-6-yl)methyl]-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-({2-[(3-ethoxyazetidin-1-yl)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-{[2-({2-azaspiro[3.5]nonan-2-yl}methyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-({2-[(2-methylazetidin-1-yl)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-({2-[(3,3-dimethylpyrrolidin-1-yl)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-{[2-({6-fluoro-2-azaspiro[3.3]heptanean-2-yl}methyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-{[2-({6,6-difluoro-2-azaspiro[3.3]heptanean-2-yl}methyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-({2-[(3-cyclobutylazetidin-1-yl)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-({2-[(3-cyclopropylazetidin-1-yl)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-({2-[(3-tert-butylazetidin-1-yl)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[(2-{[(1-tert-butylcyclopropyl)amino]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-{[2-({[(3-methylcyclobutyl)methyl]amino}methyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   4-oxo-N-[(2-{[(2,3,3-trimethylbutan-2-yl)amino]methyl}-1H-indol-6-yl)methyl]-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[(2-{[({imidazo[1,2-a]pyridin-2-yl}methyl)amino]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-({2-[(3,3-diethylazetidin-1-yl)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   4-oxo-N-[(2-{[(pent-3-yn-1-yl)amino]methyl}-1H-indol-6-yl)methyl]-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-{[2-({6-azaspiro[3.4]octan-6-yl}methyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-({2-[(2,2-dimethylpyrrolidin-1-yl)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-{[2-({octahydrocyclopenta[c]pyrrol-2-yl}methyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-{[2-({5-azaspiro[2.4]heptanean-5-yl}methyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[(2-{[({3-methoxybicyclo[1.1.1]pentan-1-yl}methyl)amino]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   4-oxo-N-[(2-{[({spiro[2.2]pentan-1-yl}methyl)amino]methyl}-1H-indol-6-yl)methyl]-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   4-oxo-N-({2-[({spiro[2.3]hexan-1-yl}amino)methyl]-1H-indol-6-yl}methyl)-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[(2-{[({3-cyanobicyclo[1.1.1]pentan-1-yl}methyl)amino]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-{[2-({1-oxa-6-azaspiro[3.4]octan-6-yl}methyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-{[2-({2-azaspiro[4.4]nonan-2-yl}methyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[(2-{[(1-methylcyclopentyl)amino]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-{[2-(hydroxymethyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[(2-{[(1-cyclobutylcyclopropyl)amino]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-{[2-({[(1-methylcyclobutyl)methyl]amino}methyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   4-oxo-N-[(2-{[({spiro[2.3]hexan-5-yl}methyl)amino]methyl}-1H-indol-6-yl)methyl]-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-({2-[({[3-(fluoromethyl)bicyclo[1.1.1]pentan-1-yl]methyl}amino)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[(2-{[(1-{3-fluorobicyclo[1.1.1]pentan-1-yl}ethyl)amino]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-({2-[(tert-butylamino)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   4-(1-{[2-({2-azaspiro[3.3]heptanean-2-yl}methyl)-1H-indol-6-yl]methyl}-1H-1,2,3-triazol-4-yl)-1H-indazole-   N-{[2-(2-{2-azaspiro[3.3]heptanean-2-yl}ethyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   ({3-fluorobicyclo[1.1.1]pentan-1-yl}methyl)({6-[(4-{imidazo[1,5-a]pyridin-8-yl}-1H-1,2,3-triazol-1-yl)methyl]-1H-indol-2-yl}methyl)amine-   N-[(2-{[({3-fluorobicyclo[1.1.1]pentan-1-yl}methyl)amino]methyl}-1H-indol-6-yl)methyl]-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-7-carboxamide-   N-[(2-{[({bicyclo[1.1.1]pentan-1-yl}methyl)amino]methyl}-1H-pyrrolo[3,2-b]pyridin-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[(2-{[({3-fluorobicyclo[1.1.1]pentan-1-yl}methyl)amino]methyl}-1H-pyrrolo[3,2-b]pyridin-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[(2-{[(cyclobutylmethyl)amino]methyl}-1H-pyrrolo[3,2-b]pyridin-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[(2-{[({3-methylbicyclo[1.1.1]pentan-1-yl}methyl)amino]methyl}-1H-pyrrolo[3,2-c]pyridin-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[(2-{[(cyclobutylmethyl)amino]methyl}-1H-pyrrolo[3,2-c]pyridin-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[(2-{[({bicyclo[1.1.1]pentan-1-yl}methyl)amino]methyl}-1H-pyrrolo[3,2-c]pyridin-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[(2-{[({3-fluorobicyclo[1.1.1]pentan-1-yl}methyl)amino]methyl}-1H-pyrrolo[3,2-c]455yridine-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[(2-{[(cyclobutylmethyl)amino]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H,6H,7H,8H,9H-pyrido[1,2-a]pyrimidine-2-carboxamide    (cyclobutylmethyl)({6-[(4-{1H-pyrrolo[2,3-b]pyridin-5-yl}-1H-imidazol-1-yl)methyl]-1H-indol-2-yl}methyl)amine    (cyclobutylmethyl)({6-[(4-{imidazo[1,5-a]pyridin-8-yl}-1H-1,2,3-triazol-1-yl)methyl]-1H-indol-2-yl}methyl)amine-   N-[(2-{[(2,2-dimethylpropyl)amino]methyl}-1H-indol-6-yl)methyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxamide-   N-[(2-{[(cyclobutylmethyl)amino]methyl}-1H-indol-6-yl)methyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxamide-   (cyclobutylmethyl)({6-[(4-{1H-pyrrolo[2,3-b]pyridin-5-yl}-1H-1,2,3-triazol-1-yl)methyl]-1H-indol-2-yl}methyl)amine-   N-[[2-(2-azabicyclo[2.2.1]heptanean-2-ylmethyl)-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[(3-fluoro-1-bicyclo[1.1.1]pentanyl)methyl]-1-[6-[(4-imidazo[1,5-a]pyridin-8-yltriazol-1-yl)methyl]-1H-pyrrolo[3,2-c]pyridin-2-yl]methanamine-   (cyclobutylmethyl)[(6-{[1-(1H-indazol-4-yl)-1H-1,2,3-triazol-4-yl]methyl}-1H-indol-2-yl)methyl]amine-   [(3,3-difluorocyclobutyl)methyl][(6-{[1-(1H-indazol-4-yl)-1H-1,2,3-triazol-4-yl]methyl}-1H-indol-2-yl)methyl]amine-   (cyclobutylmethyl)[(6-{[1-(isoquinolin-4-yl)-1H-1,2,3-triazol-4-yl]methyl}-1H-indol-2-yl)methyl]amine-   (cyclobutylmethyl)({6-[(1-{imidazo[1,5-a]pyridin-8-yl}-1H-1,2,3-triazol-4-yl)methyl]-1H-indol-2-yl}methyl)amine.-   3-[1-({2-[({(Bicyclo[1.1.1]pent-1-yl)methyl}amino)methyl]-1H-indol-6-yl}methyl)-1H-1,2,3-triazol-4-yl]-5-methoxy-2-pyridinecarbonitrile;-   3-[1-({2-[({(3-Fluorobicyclo[1.1.1]pent-1-yl)methyl}amino)methyl]-1H-indol-6-yl}methyl)-1H-1,2,3-triazol-4-yl]-5-methoxy-2-pyridinecarbonitrile;-   5-Methoxy-3-[1-({2-[({(3-methylbicyclo[1.1.1]pent-1-yl)methyl}amino)methyl]-1H-indol-6-yl}methyl)-1H-1,2,3-triazol-4-yl]-2-pyridinecarbonitrile;-   3-{1-[(2-{[(Cyclobutylmethyl)amino]methyl}-1H-indol-6-yl)methyl]-1H-1,2,3-triazol-4-yl}-5-methoxy-2-pyridinecarbonitrile;-   3-{1-[(2-{(6-Aza-6-spiro[3.4]octyl)methyl}-1H-indol-6-yl)methyl]-1H-1,2,3-triazol-4-yl}-5-methoxy-2-pyridinecarbonitrile;-   3-[1-({2-[(4,4-Dimethyl-1-piperidyl)methyl]-1H-indol-6-yl}methyl)-1H-1,2,3-triazol-4-yl]-5-methoxy-2-pyridinecarbonitrile;-   N-((2-((6-azaspiro[3.4]octan-6-yl)methyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide;-   3-(1-((2-(((cyclobutylmethyl)amino)methyl)-1H-indol-6-yl)methyl)-1H-1,2,3-triazol-4-yl)-5-fluoropicolinonitrile;-   1-cyclobutyl-N-((6-((4-(5-methoxypyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)-1H-indol-2-yl)methyl)methanamine;-   5-chloro-3-(1-((2-(((cyclobutylmethyl)amino)methyl)-1H-indol-6-yl)methyl)-1H-1,2,3-triazol-4-yl)picolinonitrile;    and-   2-((6-azaspiro[3.4]octan-6-yl)methyl)-6-((4-(imidazo[1,5-a]pyridin-8-yl)-1H-1,2,3-triazol-1-yl)methyl)-1H-pyrrolo[3,2-c]pyridine.    48. A compound, or a pharmaceutically acceptable salt thereof,    selected from any one of the following:-   N-[[2-[[(1-hydroxycyclobutyl)methylamino]methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide;-   N-[[2-[[(1-fluorocyclobutyl)methylamino]methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide;-   N-[[2-[(4,4-dimethyl-1-piperidyl)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[[2-[(cyclobutylmethylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[[2-[(cyclobutylmethylamino)methyl]-1H-indol-6-yl]methyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxamide-   N-(cyclobutylmethyl)-1-[6-[[4-(1H-pyrazolo[4,3-c]pyridin-4-yl)triazol-1-yl]methyl]-1H-indol-2-yl]methanamine-   N-(cyclobutylmethyl)-1-[6-[[4-(1H-indazol-4-yl)triazol-1-yl]methyl]-1H-indol-2-yl]methanamine-   N-(cyclobutylmethyl)-1-[6-[[4-(1H-pyrrolo[2,3-b]pyridin-5-yl)triazol-1-yl]methyl]-1H-indol-2-yl]methanamine-   N-[[2-[(2,2-dimethylpropylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[[2-[(1-bicyclo[1.1.1]pentanylmethylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide-   1-[[[6-[[4-(1H-indazol-4-yl)triazol-1-yl]methyl]-1H-indol-2-yl]methylamino]methyl]cyclobutanol-   N-[[2-[[(3-fluoro-1-bicyclo[1.1.1]pentanyl)methylamino]methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[[2-[[(3,3-difluorocyclobutyl)methylamino]methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[(3,3-difluorocyclobutyl)methyl]-1-[6-[[1-(1H-indazol-4-yl)triazol-4-yl]methyl]-1H-indol-2-yl]methanamine-   N-[[2-[(oxetan-2-ylmethylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[[2-[(cyclobutylmethylamino)methyl]-1H-indol-6-yl]methyl]-1H-indazole-4-carboxamide-   N-[[2-[[(1-fluorocyclobutyl)methylamino]methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[[2-[(cyclobutylmethylamino)methyl]-3H-benzimidazol-5-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-(cyclobutylmethyl)-1-[6-[[1-(4-isoquinolyl)triazol-4-yl]methyl]-1H-indol-2-yl]methanamine-   4-oxo-N-[[2-[(prop-2-ynylamino)methyl]-1H-indol-6-yl]methyl]pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[[2-[(2,2-dimethylpropylamino)methyl]-1H-indol-6-yl]methyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxamide-   N-[[2-[(cyclopropylmethylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[[2-[(isobutylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide-   N-[[2-[(cyclohexylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide.    49. A pharmaceutical composition comprising a compound according to    any one of paragraphs 1 to 48, or a pharmaceutically acceptable salt    thereof, and one or more pharmaceutically acceptable excipients.    50. A compound according to any one of paragraphs 1 to 48, or a    pharmaceutically acceptable salt thereof, or a pharmaceutical    composition according to paragraph 49, for use in therapy.    51. A compound according to any one of paragraphs 1 to 47, or a    pharmaceutically acceptable salt thereof, or a pharmaceutical    composition according to paragraph 49, for use in the treatment of a    proliferative condition.    52. A compound according to any one of paragraphs 1 to 48, or a    pharmaceutically acceptable salt thereof, or a pharmaceutical    composition according to paragraph 49, for use in the treatment of    cancer.    53. A compound according to any one of paragraphs 1 to 48, or a    pharmaceutically acceptable salt thereof, or a pharmaceutical    composition according to paragraph 49, for use in the treatment of    leukaemia.    54. A compound according to any one of paragraphs 1 to 48, or a    pharmaceutically acceptable salt thereof, or a pharmaceutical    composition according to paragraph 49, for use in the treatment of    AML leukaemia or chronic myeloid leukaemia.    55. A compound according to any one of paragraphs 1 to 48, or a    pharmaceutically acceptable salt thereof, or a pharmaceutical    composition according to paragraph 49, for use in the inhibition of    METTL3 activity.    56. A compound according to any one of paragraphs 1 to 48, or a    pharmaceutically acceptable salt thereof, or a pharmaceutical    composition according to paragraph 49, for use in the treatment of    an autoimmune disease, a neurological disease, an inflammatory    disease or an infectious disease.    57. Use of a compound according to any one of paragraphs 1 to 48, or    a pharmaceutically acceptable salt thereof, in the manufacture of a    medicament for the treatment of a proliferative condition.    58. Use of a compound according to any one of paragraphs 1 to 48, or    a pharmaceutically acceptable salt thereof, in the manufacture of a    medicament for the treatment of cancer.    59. Use of a compound according to any one of paragraphs 1 to 48, or    a pharmaceutically acceptable salt thereof, in the manufacture of a    medicament for the treatment of leukaemia.    60. Use of a compound according to any one of paragraphs 1 to 48, or    a pharmaceutically acceptable salt thereof, in the manufacture of a    medicament for the treatment of AML leukaemia or chronic myeloid    leukaemia.    61. Use of a compound according to any one of paragraphs 1 to 48, or    a pharmaceutically acceptable salt thereof, in the manufacture of a    medicament for the treatment of an autoimmune disease, a    neurological disease, an inflammatory disease or an infectious    disease.    62. Use of a compound according to any one of paragraphs 1 to 48, or    a pharmaceutically acceptable salt thereof, in the manufacture of a    medicament for the inhibition of METTL3 activity.    63. A method of treating a proliferative disorder, said method    comprising administering to a subject in need thereof a    therapeutically effective amount of a compound according to any one    of paragraphs 1 to 48, or a pharmaceutically acceptable salt    thereof, or a pharmaceutical composition according to paragraph 49.    64. A method of treating cancer, said method comprising    administering to a subject in need thereof a therapeutically    effective amount of a compound according to any one of paragraphs 1    to 45, or a pharmaceutically acceptable salt thereof, or a    pharmaceutical composition according to paragraph 46.    65. A method of treating leukaemia, said method comprising    administering to a subject in need thereof a therapeutically    effective amount of a compound according to any one of paragraphs 1    to 48, or a pharmaceutically acceptable salt thereof, or a    pharmaceutical composition according to paragraph 49.    66. A method of treating AML leukaemia or chronic myeloid leukaemia,    said method comprising administering to a subject in need thereof a    therapeutically effective amount of a compound according to any one    of paragraphs 1 to 48, or a pharmaceutically acceptable salt    thereof, or a pharmaceutical composition according to paragraph 49.    67. A method of treating an autoimmune disease, a neurological    disease, an inflammatory disease or an infectious disease, said    method comprising administering to a subject in need thereof a    therapeutically effective amount of a compound according to any one    of paragraphs 1 to 48, or a pharmaceutically acceptable salt    thereof, or a pharmaceutical composition according to paragraph 49.    68. A method of inhibiting METTL3 activity in vitro or in vivo, said    method comprising contacting a cell with an effective amount of a    compound according to any one of paragraphs 1 to 48, or a    pharmaceutically acceptable salt thereof, or a pharmaceutical    composition according to paragraph 49.    69. A method of inhibiting metastasis in vitro or in vivo, said    method comprising contacting a cell with an effective amount of a    compound according to any one of paragraphs 1 to 48, or a    pharmaceutically acceptable salt thereof, or a pharmaceutical    composition according to paragraph 49.

1. A compound of formula (I) shown below, or a pharmaceuticallyacceptable salt thereof:X—Y—Z  (I) wherein: X is selected from:

wherein Q₁ is selected from NH, N—C₁₋₄alkyl, O or S; Q_(2a) is selectedfrom N or CR₂a; Q_(2b) is selected from N or CR_(2b); Q_(2c) is selectedfrom N or CR₂c; Q_(2d) is selected from N or CR_(2d); Q₃ is selectedfrom N or CR_(1b); Q₄ is selected from N or CR_(1x); subject to theproviso that no more than 3 of Q₁, Q_(2a), Q_(2b), Q_(2c), Q_(2d), Q₃and Q₄ are nitrogen; R_(1a) is selected from: (i) C₁₋₄alkyl orC₁₋₄alkoxy, each of which being optionally substituted by halo, cyano,hydroxy, C₃₋₆cycloalkyl, a 3 to 6 membered heterocyclyl C₁₋₄alkoxy,C₁₋₄haloalkoxy, aryl or heteroaryl; or (ii) a group of the formula:—(CR_(1c)R_(1d))_(p)—NR_(1e)R_(1f); wherein p is an integer selectedfrom 0, 1, 2 or 3 R_(1c) and R_(1d) are independently selected from: (i)hydrogen (including deuterium), (ii) C₁₋₆alkyl which is optionallysubstituted by one more substituents selected from cyano, oxo, hydroxy,C₁₋₄alkoxy, halo, C₁₋₄haloalkoxy, C₃₋₆cycloalkyl, —O—C₃₋₆cycloalkyl,NR_(1ca)R_(1da) or —S(O)₀₋₂R_(1ca)R_(1da), wherein R_(1ca) and R_(1da)are H or C₁₋₂alkyl; and wherein C₃₋₆cycloalkyl and —O—C₃₋₆cycloalkyl areoptionally further substituted with halo, cyano or hydroxy; (iii)C₃₋₄cycloalkyl or 3 to 5 membered heterocyclyl, each of which isoptionally substituted by C₁₋₄alkyl, C₁₋₄haloalkyl, cyano, hydroxy,C₁₋₂alkoxy, halo, C₁₋₂haloalkoxy, NR_(1ca)R_(1da) or—S(O)₀₋₂R_(1ca)R_(1da), wherein R_(1ca) and R_(1da) are H or C₁₋₂alkyl;(iv) or R_(1c) and R_(1d) are linked together such that, together withthe carbon atom to which they are attached, they form a 3- to 6-memberedcycloalkyl or heterocyclic ring, or a spirocyclic ring system, each ofwhich is optionally substituted by one or more substituents selectedfrom C₁₋₂alkyl, C₁₋₂haloalkyl, cyano, hydroxy, C₁₋₂alkoxy, halo,C₁₋₂haloalkoxy, NR_(1ca)R_(1da) or —S(O)₀₋₂R_(1ca)R_(1da), whereinR_(1ca) and R_(1da) are H or C₁₋₂alkyl; R_(1e) and R_(1f) are eachindependently selected from: (i) hydrogen (including deuterium); (ii)C₁₋₆alkyl which is optionally substituted by one more substituentsselected from cyano, oxo, hydroxy, C₁₋₂alkoxy, halo, C₁₋₂haloalkoxy,NR_(1ea)R_(1fa) or —S(O)₀₋₂R_(1ea)R_(1fa), wherein R_(1ea) and R_(1fa)are H or C₁₋₂alkyl; (iii) a group with the formula:—(CR_(1g)R_(1h))_(q)-T₁ wherein: q is 0, 1, 2, 3, 4, 5 or 6; R_(1g) andR_(1h) are independently selected from: a) hydrogen; b) C₁₋₆alkyl whichis optionally substituted by one more substituents selected from cyano,hydroxy, C₁₋₄alkoxy, halo, C₁₋₄haloalkoxy, —O—C₃₋₆cycloalkyl,NR_(1ga)R_(1ha) or —S(O)₀₋₂R_(1ga)R_(1ha), wherein R_(1ga) and R_(1ha)are H or C₁₋₂alkyl; and wherein —O—C₃₋₆cycloalkyl is optionallysubstituted with halo, cyano or hydroxy; c) an aryl-C₁₋₆alkyl,heteroarylC₁₋₆alkyl, C₃₋₆cycloalkyl or C₃₋₆-cycloalkylC₁₋₆alkyl group,each of which is optionally substituted by one or more substituentsselected from C₁₋₂-alkyl, cyano, C₁₋₂haloalkyl, hydroxy, C₁₋₂alkoxy,halo, C₁₋₂-haloalkoxy, NR_(1ga)R_(1ha) or —S(O)₀₋₂R_(1ga)R_(1ha),wherein R_(1ga) and R_(1ha) are H or C₁₋₂alkyl; or d) R_(1g) and R_(1h)are optionally linked together such that, together with the carbon atomto which they are attached, they form a 3- to 6-membered cycloalkyl orheterocyclic ring which is optionally substituted by one or moresubstituents selected from C₁₋₂alkyl, cyano, C₁₋₂haloalkyl, hydroxy,C₁₋₂alkoxy, halo, C₁₋₂haloalkoxy, NR_(1ga)R_(1ha) or—S(O)₀₋₂R_(1ga)R_(1ha), wherein R_(1ga) and R_(1ha) are H or C₁₋₂alkyl;and T₁ is selected from hydrogen, halo, C₁₋₄alkyl, C₁₋₄haloalkyl, cyano,hydroxy, NR_(1t)R_(2t) or —S(O)₀₋₂R_(1t)R_(2t) (wherein R_(1t) andR_(2t) are H or C₁₋₄alkyl), C₃₋₈cycloalkyl, C₂₋₃alkenyl, C₂₋₃alkynyl,aryl, heterocyclyl, a mono- or bicyclic heteroaryl, a spirocycliccarbocyclic or heterocyclic ring system, a bridged C₃₋₈cycloalkyl, abridged bicyclic C₅₋₁₂cycloalkyl, or a bridged heterocyclic ring system,each of which is optionally substituted by one or more substituentsselected from C₁₋₂alkyl, C₁₋₂haloalkyl, cyano, hydroxy, C₁₋₂alkoxy,halo, C₁₋₂-haloalkoxy, C₃₋₆cycloalkyl, NR_(3t)R_(4t) or—S(O)₀₋₂R_(3t)R_(4t), wherein R_(3t) and R_(4t) are H or C₁₋₂alkyl; (iv)or R_(1e) and R_(1f) are linked such that, together with the nitrogenatom to which they are attached, they form a mono- orbicyclic-heterocyclic ring, which is optionally substituted by one ormore substituents selected from C₁₋₄alkyl, C₁₋₄haloalkyl,C₃₋₆cycloalkyl, cyano, hydroxy, C₁₋₄alkoxy, halo, C₁₋₄haloalkoxy,NR_(1i)R_(1j) or —S(O)₀₋₂R_(1i)R_(1j), wherein R_(1i) and R_(1j) are Hor C₁₋₄alkyl, and/or the mono- or bicyclic hetereocyclic ring formed byR_(1e) and R_(1f) is optionally spiro-fused to a C₃₋₆cycloalkyl or aheterocyclic ring, which in turn is optionally substituted by one ormore substituents selected from C₁₋₄alkyl, C₁₋₄haloalkyl,C₃₋₆cycloalkyl, cyano, hydroxy, C₁₋₄alkoxy, halo, C₁₋₄haloalkoxy,NR_(1i)R_(1j) or —S(O)₀₋₂R_(1i)R_(1j), wherein R_(1i) and R_(1j) are Hor C₁₋₄alkyl; wherein any wherein any alkyl, alkoxy or C₃₋₆cycloalkyl isfurther optionally substituted by one or more substituents selected fromcyano, hydroxy, halo, NR_(1k)R_(1l) or —S(O)₀₋₂R_(1k)R_(1l), whereinR_(1k) and R_(1l) are H or C₁₋₄alkyl R_(1b) is selected from hydrogen,cyano, halo or C₁₋₃ alkyl; R_(1x) is selected from hydrogen, cyano, haloor C₁₋₃ alkyl; R_(2a), R_(2b), R_(2c) and R_(2d) are independentlyselected from hydrogen, cyano, halo or a group of the formula:-L_(2a)-L_(2b)-Q₂ wherein L_(2a) is absent or C₁₋₃alkylene optionallysubstituted by C₁₋₂ alkyl or oxo; L_(2b) is absent or selected from O,S, SO, SO₂, N(R_(n)), C(O), C(O)O, OC(O), C(O)N(R_(n)), N(R_(n))C(O),N(R_(n))C(O)N(R_(o)), S(O)₂N(R_(n)), or N(R_(n))SO₂, wherein R_(n) andR_(o) are each independently selected from hydrogen or C₁₋₂alkyl; and Q₂is hydrogen, cyano, C₁₋₆alkyl, C₃₋₆cycloalkyl, aryl, heterocyclyl orheteroaryl, each of which is optionally substituted by one or moresubstituents selected from halo, trifluoromethyl, trifluoromethoxy,amino, cyano, hydroxy, amino, carboxy, carbamoyl, sulphamoyl, C₁₋₄alkyl,NR_(p)R_(q), OR_(p), C(O)R_(p), C(O)OR_(p), OC(O)R_(p),C(O)N(R_(p))R_(q), N(R_(r))C(O)R_(p), S(O)_(y)R_(p) (where y is 0, 1 or2), SO₂N(R_(p))R_(q), N(R_(r))SO₂R_(p) or (CH₂)_(z)NR_(p)R_(q) (where zis 1, 2 or 3), wherein R_(p) and R_(q) are each independently selectedfrom hydrogen or C₁₋₄alkyl; Y is selected from:

wherein: R_(3a1), R_(3b1), R_(3c1), R_(3d1), R_(3e1), R_(3f1), R_(3g1),R_(3h1), R_(3i1), R_(3j1), R_(3k1), R_(3l1), R_(3m1), R_(3n1), R_(3o1),R_(3p1), R_(3q1), R_(3r1) and R_(3s1) are independently selected fromhydrogen (including deuterium), C₁₋₆alkyl, C₃₋₄ cycloalkyl, hydroxy, andhalo; and wherein C₁₋₆alkyl, or C₃₋₄ cycloalkyl is optionallysubstituted with one or more substituents selected from halo, amino,cyano, and hydroxy; R_(3a2), R_(3b2), R_(3c2), R_(3d2), R_(3e2),R_(3f2), R_(3g2), R_(3h2), R_(3i2), R_(3j2), R_(3k2), R_(3l2), R_(3m2),R_(3n2), R_(3o2), R_(3p2), R_(3q2), R_(3r2) and R_(3s2) are hydrogen orhalo; with the proviso that R_(3a1), R_(3b1), R_(3i1), R_(3l1), R_(3o1),R_(3r1), R_(3a2), R_(3b2), R_(3i2), R_(3l2), R_(3o2) and R_(3s1) cannotbe halo when n=1 or when n=2 and the carbon atom to which they areattached is linked to an oxygen or nitrogen atom; or R_(3a1) andR_(3a2), R_(3b1) and R_(3b2), R_(3c1) and R_(3c2), R_(3d1) and R_(3d2),R_(3e1) and R_(3e2), R_(3f1) and R_(3f2), R_(3g1) and R_(3g2), R_(3h1)and R_(3h2), R_(3i1) and R_(3i2), R_(3j1) and R_(3j2), R_(3k1) andR_(3k2), R_(3l1) and R_(3l2), R_(3m1) and R_(3m2), R_(3n1) and R_(3n2),R_(3o1) and R_(3o2), R_(3p1) and R_(3p2), R_(3q1) and R_(3q2), orR_(3r1) and R_(3r2) or R_(3s1) and R_(3s2) may be linked such that,together with the carbon atom to which they are attached, they form aspiro-fused C₃₋₄cycloalkyl which is optionally substituted with one ormore substituents selected from halo, methyl, amino, cyano, and hydroxy;n is 0, 1 or 2 Z is selected from:

wherein: R₄ is selected from hydrogen, halo, cyano, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₁₋₄alkoxy, C₁₋₄ haloalkoxy (e.g. hydrogen, halo, cyano andmethyl); R₅ is selected from hydrogen, halo, cyano, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₁₋₄alkoxy, C₁₋₄ haloalkoxy (e.g. hydrogen, halo, cyano andmethyl); R₆ is selected from hydrogen, halo, cyano, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₁₋₄alkoxy, C₁₋₄ haloalkoxy (e.g. hydrogen, halo, cyano andmethyl); R₈, R₉, R₁₀ and R₁₁ are independently selected from hydrogen,NH₂, halo, cyano, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, C₁₋₆ alkyl, —CH₂OCH₃,—CH₂SO₂CH₃, —SO₂CH₃, —NHC(O)CH₃ and —C(O)NR_(v1)R_(v2), wherein R_(v1)and R_(v2) are independently selected from hydrogen and methyl; or R₉and R₁₀ may be linked together such that, together to the atoms to whichthey are attached, they form a fused 5- or 6-membered saturated orunsaturated ring system, or R₁₀ and R₁₁ may be linked together suchthat, together to the atoms to which they are attached, they form afused 5- or 6-membered saturated or unsaturated ring system, whereineither of the fused 5- or 6-membered saturated or unsaturated ringsystem may be optionally substituted by one or more substituentsselected from C₁₋₂alkyl, cyano, C₁₋₂haloalkyl, hydroxy, C₁₋₂alkoxy,halo, C₁₋₂haloalkoxy, NR_(1ia)R_(1ja) or —S(O)₀₋₂R_(1ia)R_(1ja), whereinR_(1ia) and R_(1ja) are H or C₁₋₂alky; R₇ and R_(11N) are independentlyselected from hydrogen, NH₂, halo, cyano, and C₁₋₆ alkyl; R_(Z1) andR_(Z1a) selected from hydrogen, C₁₋₄alkyl, cyano, halo, C₁₋₄haloalkyl,C₁₋₄ haloalkoxy, C₁₋₄alkoxy, C₃₋₆cycloalkyl and —O—C₃₋₆cycloalkyl,wherein C₃₋₆cycloalkyl and —O—C₃₋₆cycloalkyl are optionally substitutedby one or more of halo, methyl or methoxy; R_(Z2) and R_(Z2a) areselected from hydrogen, C₁₋₄alkyl, cyano, halo, NH₂ and C₁₋₄alkoxy;R_(Z3a) is selected from hydrogen, C₁₋₄alkyl, cyano, halo, NH₂ andC₁₋₄alkoxy; R_(Zi1b) is selected from hydrogen, C₁₋₄alkyl, cyano, halo,NH₂ and C₁₋₄alkoxy; R_(Zi2e) is selected from hydrogen, C₁₋₄alkyl,cyano, halo, NH₂ and C₁₋₄alkoxy; R_(Y5N) and R_(Z2N) are selected fromhydrogen or C₁₋₄alkyl; R_(Z9) is selected from hydrogen, halo, cyano,C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄alkoxy, C₁₋₄ haloalkoxy; R_(Z10) isselected from hydrogen, halo, cyano, C₁₋₄ alkyl, C₁₋₄ haloalkyl,C₁₋₄alkoxy, C₁₋₄ haloalkoxy; R_(Z11) is selected from hydrogen, halo,cyano, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄alkoxy, C₁₋₄ haloalkoxy; R_(Z12)is selected from hydrogen, halo, cyano, C₁₋₄ alkyl, C₁₋₄ haloalkyl,C₁₋₄alkoxy, C₁₋₄ haloalkoxy; R_(Z13) is selected from hydrogen, halo,cyano, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄alkoxy, C₁₋₄ haloalkoxy; R_(Z14)is selected from hydrogen, halo, cyano, C₁₋₄ alkyl, C₁₋₄ haloalkyl,C₁₋₄alkoxy, C₁₋₄ haloalkoxy; R_(Z15) is selected from hydrogen, halo,cyano, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄alkoxy, C₁₋₄ haloalkoxy; R_(Z16)is selected from hydrogen, halo, cyano, C₁₋₄ alkyl, C₁₋₄ haloalkyl,C₁₋₄alkoxy, C₁₋₄ haloalkoxy; A₁ is selected from CR₁₂ and N; A₂ isselected from CR₁₃ and N; A₅ is selected from CR₁₆ and N; A₆ is selectedfrom CR₁₇ and N; A₇ is selected from CR₁₈ and N; A₈ is selected fromCR₁₉R₂₀ and NR₂₁; A₉ is selected from CR₂₂R₂₃ and NR₂₄; A₁₁ is selectedfrom CR₂₈R₂₉ and NR₃₀; R₁₂ is selected from hydrogen, halo, cyano, C₁₋₄alkyl, C₁₋₄ haloalkyl, C₁₋₄alkoxy, C₁₋₄ haloalkoxy (e.g. hydrogen, halo,cyano and C₁₋₄ alkyl); R₁₃ is selected from hydrogen, halo, cyano, C₁₋₄alkyl, C₁₋₄ haloalkyl, C₁₋₄alkoxy, C₁₋₄ haloalkoxy (e.g. hydrogen, halo,cyano, methoxy and methyl); R₁₆ and R₁₈ are selected from hydrogen,halo, cyano, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄haloalkyl, C₁₋₄haloalkoxy,C₃₋₄cycloalkyl, a 3- to 4-membered heterocyclyl and C₃₋₄-cycloalkoxy;R₁₇ is selected from hydrogen, halo, cyano, C₁₋₄ alkyl, C₁₋₄ haloalkyl,C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, C₂₋₄ alkenyl, C₂₋₄ alkynyl, phenyl, a 5-or 6-membered or heteroaryl, C₃₋₆cycloalkyl, —O—C₃₋₆cycloalkyl,heterocyclyl, —O-heterocyclyl (carbon-linked), —(OCH₂CH₂)_(m)—OCH₃wherein m is an integer from 1 to 6, NR_(q)R_(r), wherein R_(q) andR_(r) are each independently hydrogen, C₁₋₅ alkyl, C₃₋₆cycloalkyl, a 3-to 6-membered carbon-linked heterocyclyl, or R_(q) and R_(r) are linkedtogether such that, together with the nitrogen atom to which they areattached, they form a 3- to 6-membered heterocyclic ring; wherein anyC₁₋₅alkyl, C₁₋₄ alkoxy, C₂₋₄alkenyl, C₂₋₄alkynyl, phenyl, 5- or6-membered or heteroaryl, C₃₋₆cycloalkyl, —O—C₃₋₆cycloalkyl,heterocyclyl or —O— heterocyclyl (carbon-linked) is optionally furthersubstituted by one or more substituents selected from C₁₋₂alkyl, cyano,C₁₋₂haloalkyl, hydroxy, C₁₋₂alkoxy, halo, C₁₋₂haloalkoxy,NR_(1ea)R_(1fa) or —S(O)₀₋₂R_(1ea)R_(1fa), wherein R_(1ea) and R_(1fa)are H or C₁₋₂alkyl; R₁₉ and R₂₀ are selected from hydrogen, halo, cyanoand C₁₋₄ alkyl; R₂₂ and R₂₃ are selected from hydrogen, halo, cyano,C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄alkoxy, C₁₋₄ haloalkoxy (e.g. hydrogen,halo, cyano and methyl; R₂₈ and R₂₉ are selected from hydrogen, halo,methoxy and methyl; R₂₁, R₂₄ and R₃₀ are hydrogen or C₁₋₄alkyl.
 2. Acompound according to claim 1, or a pharmaceutically acceptable saltthereof, wherein X is selected from:

wherein Q₁, R_(1a), R_(1b), R_(1x), R_(2a), R_(2b), R_(2c), R_(2d) areas defined in claim
 1. 3. A compound according to claim 1 or claim 2,wherein X is selected from:

wherein Q₁, R_(1a), R_(1b), R_(2a), R_(2b) and R_(2d) are as defined inclaim
 1. 4. A compound according to any one of claims 1 to 3, or apharmaceutically acceptable salt thereof, wherein Q₁ is selected from NHor N—C₁₋₄alkyl.
 5. A compound according to claim 1 or claim 2, or apharmaceutically acceptable salt thereof, wherein X is selected from:

wherein R_(1a) is as defined in claim 1 or claim
 2. 6. A compoundaccording to any one of the preceding claims, or a pharmaceuticallyacceptable salt thereof, wherein R_(1a) is selected from: (i) C₁₋₄alkyloptionally substituted by halo, cyano, hydroxy, C₃₋₆cycloalkyl, a 3 to 6membered heterocyclyl, C₁₋₄alkoxy, C₁₋₄haloalkoxy, aryl or heteroaryl;or (ii) a group of the formula:—(CR_(1c)R_(1a))_(p)—NR_(1e)R_(1f) wherein p is an integer selected from1 or 2; R_(1c) and R_(1d) are independently selected from: (i) hydrogen(including deuterium), (ii) C₁₋₃alkyl which is optionally substituted byone more substituents selected from cyano, oxo, hydroxy, C₁₋₄alkoxy,halo, C₁₋₄haloalkoxy, —O—C₃₋₆cycloalkyl, NR_(1ca)R_(1da) or—S(O)₀₋₂R_(1ca)R_(1da), wherein R_(1ca) and R_(1da) are H or C₁₋₂alkyl;and wherein —O—C₃₋₆cycloalkyl is optionally substituted with halo, cyanoor hydroxy; (iii) or R_(1c) and R_(1d) are linked together such that,together with the carbon atom to which they are attached, they form a 3-to 5-membered cycloalkyl or heterocyclic ring, or a spirocyclic ringsystem, each of which is optionally substituted by one or moresubstituents selected from C₁₋₂alkyl, C₁₋₂haloalkyl, cyano, hydroxy,C₁₋₂alkoxy, halo, C₁₋₂-haloalkoxy, NR_(1ca)R_(1da) or—S(O)₀₋₂R_(1ca)R_(da), wherein R_(1ca) and R_(1da) are H or C₁₋₂alkyl;R_(1e) and R_(1f) are each independently selected from: (i) hydrogen(including deuterium); (ii) C₁₋₆alkyl which is optionally substituted byone more substituents selected from cyano, oxo, hydroxy, C₁₋₂alkoxy,halo, C₁₋₂haloalkoxy, NR_(1ea)R_(1fa) or —S(O)₀₋₂R_(1ea)R_(1fa), whereinR_(1ea) and R_(1fa) are H or C₁₋₂alkyl; (iii) a group with the formula:—(CR_(1g)R_(1h))_(q)-T₁ wherein: q is 0, 1, 2 or 3; R_(1g) and R_(1h)are independently selected from: a) hydrogen (including deuterium); orb) C₁₋₃alkyl which is optionally substituted by one more substituentsselected from cyano, oxo, hydroxy, C₁₋₃alkoxy, halo, C₁₋₄haloalkoxy,—O—C₃₋₄cycloalkyl, wherein —O—C₃₋₄cycloalkyl is optionally substitutedwith halo, cyano or hydroxy, NR_(1ca)R_(1da) or —S(O)₀₋₂R_(1ca)R_(1da),wherein R_(1ca) and R_(1da) are H or C₁₋₂alkylNR_(1ga)R_(1ha) or—S(O)₀₋₂R_(1ga)R_(1ha), wherein R_(1ga) and R_(1ha) are H or C₁₋₂alkyl;or c) or R_(1g) and R_(1h) are optionally linked together such that,together with the carbon atom to which they are attached, they form a 3-to 6-membered cycloalkyl or heterocyclic ring which is optionallysubstituted by one or more substituents selected from C₁₋₂alkyl,C₁₋₂-haloalkyl, cyano, hydroxy, C₁₋₂alkoxy, halo, C₁₋₂-haloalkoxy,NR_(1ga)R_(1ha) or —S(O)₀₋₂R_(1ga)R_(1ha), wherein R_(1ga) and R_(1ha)are H or C₁₋₂alkyl; and T₁ is selected from hydrogen, halo, C₁₋₄alkyl,C₁₋₄haloalkyl, cyano, hydroxy, NR_(1t)R_(2t) or —S(O)₀₋₂R_(1t)R_(2t)(wherein R_(1t) and R_(2t) are H or C₁₋₄alkyl), C₃₋₈cycloalkyl,C₂₋₃alkenyl, C₂₋₃alkynyl, aryl, heterocyclyl, a mono- or bicyclicheteroaryl, a spirocyclic carbocyclic or heterocyclic ring system, abridged C₃₋₆cycloalkyl, a bridged bicyclic C₅₋₁₂cycloalkyl, or a bridgedheterocyclic ring system, each of which is optionally substituted by oneor more substituents selected from C₁₋₂alkyl, C₁₋₂-haloalkyl, cyano,hydroxy, C₁₋₂alkoxy, halo, C₁₋₂haloalkoxy, C₃₋₆cycloalkyl, NR_(3t)R_(4t)or —S(O)₀₋₂R_(3t)R_(4t), wherein R_(3t) and R_(4t) are H or C₁₋₂alkyl;(iv) or R_(1e) and R_(1f) are linked such that, together with thenitrogen atom to which they are attached, they form a mono- orbicyclic-heterocyclic ring, which is optionally substituted by one ormore substituents selected from C₁₋₄alkyl, C₁₋₄haloalkyl,C₃₋₆cycloalkyl, cyano, hydroxy, C₁₋₄alkoxy, halo, C₁₋₄haloalkoxy,NR_(1i)R_(1j) or —S(O)₀₋₂R_(1i)R_(1j), wherein R_(1i) and R_(1j) are Hor C₁₋₄alkyl, and/or the mono- or bicyclic hetereocyclic ring formed byR_(1e) and R_(1f) is optionally spiro-fused to a C₃₋₆cycloalkyl or aheterocyclic ring, which is optionally substituted by one or moresubstituents selected from C₁₋₄alkyl, C₁₋₄haloalkyl, C₃₋₆cycloalkyl,cyano, hydroxy, C₁₋₄alkoxy, halo, C₁₋₄haloalkoxy, NR_(1i)R_(1j) or—S(O)₀₋₂R_(1i)R_(1j), wherein R_(1i) and R_(1j) are H or C₁₋₄alkyl;wherein any alkyl, alkoxy or C₃₋₆cycloalkyl is further optionallysubstituted by one or more substituents selected from cyano, hydroxy,halo, NR_(1k)R_(1l) or —S(O)₀₋₂R_(1k)R_(1l), wherein R_(1k) and R_(1l)are H or C₁₋₄alkyl.
 7. A compound according to any one of the precedingclaims, or a pharmaceutically acceptable salt thereof, wherein R_(1a) isa group of the formula:—(CR_(1c)R_(1d))_(p)—NR_(1e)R_(1f) wherein p is an integer selected from1 or 2; R_(1c) and R_(1d) are independently selected from: (i) hydrogen(including deuterium), or (ii) C₁₋₃alkyl which is optionally substitutedby one more substituents selected from cyano, oxo, hydroxy, C₁₋₃alkoxy,halo, C₁₋₃haloalkoxy, —O—C₃₋₄cycloalkyl, or NH₂; wherein—O—C₃₋₆cycloalkyl is optionally substituted with halo, cyano or hydroxy,(iii) or R_(1c) and R_(1d) are linked together such that, together withthe carbon atom to which they are attached, they form a 3- to 5-memberedcycloalkyl or heterocyclic ring, or a spirocyclic ring system, each ofwhich is optionally substituted by one or more substituents selectedfrom C₁₋₂alkyl, C₁₋₂haloalkyl, cyano, hydroxy, C₁₋₂alkoxy, halo,C₁₋₂haloalkoxy, NR_(1ca)R_(1da) or —S(O)₀₋₂R_(1ca)R_(1da), whereinR_(1ca) and R_(1da) are H or C₁₋₂alkyl; R_(1e) and R_(1f) are eachindependently selected from: (i) hydrogen (including deuterium); (ii)C₁₋₆alkyl which is optionally substituted by one more substituentsselected from cyano, hydroxy, C₁₋₂alkoxy, halo, C₁₋₂haloalkoxy and NH₂;(iii) a group with the formula:—(CR_(1g)R_(1h))_(q)-T₁ wherein: q is 0, 1, 2 or 3; R_(1g) and R_(1h)are independently selected from: a) hydrogen (including deuterium); b)C₁₋₆alkyl which is optionally substituted by one more substituentsselected from cyano, hydroxy, C₁₋₄alkoxy, halo, C₁₋₄haloalkoxy,—O—C₃₋₆cycloalkyl, NR_(1ca)R_(1da) or —S(O)₀₋₂R_(1ca)R_(1da), whereinR_(1ca) and R_(1da) are H or C₁₋₂alkylNR_(1ga)R_(1ha) or—S(O)₀₋₂R_(1ga)R_(1ha), wherein R_(1ga) and R_(1ha) are H or C₁₋₂alkyl;and wherein —O—C₃₋₆cycloalkyl is optionally substituted with halo, cyanoor hydroxy; or c) or R_(1g) and R_(1h) are optionally linked togethersuch that, together with the carbon atom to which they are attached,they form a 3- to 6-membered cycloalkyl or heterocyclic ring which isoptionally substituted by one or more substituents selected fromC₁₋₂alkyl, C₁₋₂haloalkyl, cyano, hydroxy, C₁₋₂alkoxy, halo,C₁₋₂haloalkoxy, NR_(1ga)R_(1ha) or —S(O)₀₋₂R_(1ga)R_(1ha), whereinR_(1ga) and R_(1ha) are H or C₁₋₂alkyl; and T₁ is selected fromhydrogen, halo, C₁₋₄alkyl, C₁₋₄haloalkyl, cyano, hydroxy, NR_(1t)R_(2t)or —S(O)₀₋₂R_(1t)R_(2t) (wherein R_(1t) and R_(2t) are H or C₁₋₄ alkyl),C₃-cycloalkyl, C₂₋₃alkenyl, C₂₋₃alkynyl, aryl, heterocyclyl, a mono- orbicyclic heteroaryl, a spirocyclic carbocyclic or heterocyclic ringsystem, a bridged C₃₋₈cycloalkyl, a bridged bicyclic C₅₋₁₂cycloalkyl, ora bridged heterocyclic ring system, each of which is optionallysubstituted by one or more substituents selected from C₁₋₂alkyl,C₁₋₂-haloalkyl, cyano, hydroxy, C₁₋₂alkoxy, halo, C₁₋₂haloalkoxy,C₃₋₆cycloalkyl, NR_(3t)R_(4t) or —S(O)₀₋₂R_(3t)R_(4t), wherein R_(3t)and R_(4t) are H or C₁₋₂alkyl; (iv) or R_(1e) and R_(1f) are linked suchthat, together with the nitrogen atom to which they are attached, theyform a mono- or bicyclic-heterocyclic ring, which is optionallysubstituted by one or more substituents selected from C₁₋₄alkyl, C₁₋₄haloalkyl, C₃₋₆cycloalkyl, cyano, hydroxy, C₁₋₄alkoxy, halo,C₁₋₄haloalkoxy, NR_(1i)R_(1j) or —S(O)₀₋₂R_(1i)R_(1j), wherein R_(1i)and R_(1j) are H or C₁₋₄alkyl, and/or the mono- or bicyclichetereocyclic ring formed by R_(1e) and R_(1f) is optionally spiro-fusedto a C₃₋₆cycloalkyl or a heterocyclic ring, which in turn is optionallysubstituted by one or more substituents selected from C₁₋₄alkyl,C₁₋₄haloalkyl, C₃₋₆cycloalkyl, cyano, hydroxy, C₁₋₄alkoxy, halo,C₁₋₄haloalkoxy, NR_(1i)R_(1j) or —S(O)₀₋₂R_(1i)R_(1j), wherein R₁ andR_(1j) are H or C₁₋₄alkyl.
 8. A compound according to any one of thepreceding claims, or a pharmaceutically acceptable salt thereof, whereinR_(1a) is a group of the formula:—(CR_(1c)R_(1d))_(p)—NR_(1e)R_(1f) wherein R_(1c) and R_(1d) areindependently selected from hydrogen (including deuterium) or C₁₋₂alkyl; R_(1e) is selected from hydrogen (including deuterium) orC₁₋₂alkyl; and R_(1f) is a group with the formula:—(CR_(1g)R_(1h))_(q)-T₁ wherein: q is 1; R_(1g) and R_(1h) areindependently selected from hydrogen (including deuterium) or C₁₋₂alkyl;and T₁ is selected from C₃₋₄cycloalkyl, heterocyclyl, a spirocycliccarbocyclic or heterocyclic ring system, a bridged C₃₋₈cycloalkyl, abridged bicyclic C₅₋₁₂cycloalkyl, or a bridged heterocyclic ring system,each of which is optionally substituted by one or more substituentsselected from C₁₋₂alkyl, C₁₋₂haloalkyl, cyano, hydroxy, C₁₋₂alkoxy,halo, C₁₋₂haloalkoxy or C₃₋₆cycloalkyl, wherein any alkyl or alkoxy isoptionally further substituted by one or more substituents selected fromcyano, hydroxy or halo.
 9. A compound according to any one of thepreceding claims, wherein R_(1a) is a group of the formula:—(CR_(1c)R_(1d))_(p)—NR_(1e)R_(1f) wherein p is 1; R_(1c) and R_(1d) areindependently selected from hydrogen (including deuterium) or C₁₋₂alkyl;and R_(1e) and R_(1f) are linked such that, together with the nitrogenatom to which they are attached, they form a mono- orbicyclic-heterocyclic ring, which is optionally substituted by one ormore substituents selected from C₁₋₂alkyl, C₁₋₂haloalkyl,C₃₋₆cycloalkyl, cyano, hydroxy, C₁₋₂alkoxy, halo or C₁₋₂haloalkoxy,and/or the mono- or bicyclic hetereocyclic ring formed by R_(1e) andR_(1f) is optionally spiro-fused to a C₃₋₆cycloalkyl or a heterocyclicring, which in turn is optionally substituted by one or moresubstituents selected from C₁₋₂alkyl, C₁₋₂haloalkyl, cyano, hydroxy,C₁₋₂alkoxy, halo or C₁₋₂haloalkoxy.
 10. A compound according to any ofclaims 1 to 7, wherein R_(1a) is selected from


11. A compound according to any one of the preceding claims, or apharmaceutically acceptable salt thereof, wherein R_(1b) is selectedfrom hydrogen, halo or C₁₋₂ alkyl.
 12. A compound according to any oneof the preceding claims, or a pharmaceutically acceptable salt thereof,wherein R_(2a), R_(2b), R_(2c) and R_(2d) are independently selectedfrom hydrogen, cyano, halo or C₁₋₃alkyl.
 13. A compound according to anyone of the preceding claims, or a pharmaceutically acceptable saltthereof, wherein Y is selected from:


14. A compound according to any one of the preceding claims, or apharmaceutically acceptable salt thereof, wherein Z is selected from:

wherein A₁, A₂, A₅, A₆, A₇, A₈, A₉, A₁₁, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀,R₁₁, R_(11N), R₁₂, R₁₃, R₁₉, R₂₂, R_(Z1), R_(Z2), R_(Z2N), R_(Z9),R_(Z10), R_(Z11), R_(Z12), R_(Z13), R_(Z14), R_(Z15), R_(Z16), R_(Z2a),R_(Z3a), R_(Z1a), R_(Zi1b) and R_(Zi2e) are as defined in any one of thepreceding claims.
 15. A compound according to any one of the precedingclaims, or a pharmaceutically acceptable salt thereof, wherein: (i) R₄,R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R_(11a), R_(11b), R_(Z2), R_(Z2a),R_(Z3a), R_(Zi1b), R_(Zi2e), R_(Z9), R_(Z10), R_(Z11), R_(Z12),R_(Z12a), R_(Z13), R_(Z14), R_(Z15) and R_(Z16) are independentlyselected from hydrogen, methyl, cyano or halo; and R_(Y5N), R_(Z2N) andR_(11N) are selected from methyl or hydrogen; (ii) R_(Z1) and R_(Z1a)are selected from hydrogen, C₁₋₄alkyl, cyano, halo, C₁₋₄haloalkyl,C₁₋₄haloalkoxy, C₁₋₄alkoxy, C₃₋₆cycloalkyl and —O—C₃₋₆cycloalkyl; (iii)R₁₂, R₁₃, R₁₆, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, R₂₃, R₂₄ and R₃₀ areindependently selected from hydrogen, halo, cyano and methyl; (iv) R₁₇is selected from hydrogen, halo, cyano, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄alkoxy, C₁₋₄ haloalkoxy, C₂₋₄ alkenyl, C₂₋₄ alkynyl, phenyl a 5- or6-membered or heteroaryl, C₃₋₆cycloalkyl, —O—C₃₋₆cycloalkyl,heterocyclyl, —(OCH₂CH₂)_(m)—OCH₃ wherein m is an integer from 1 to 6,NR_(q)R_(r), wherein R_(q) and R_(r) are each independently hydrogen,C₁₋₄ alkyl or R_(q) and R_(r) are linked together such that, togetherwith the nitrogen atom to which they are attached, they form a 3- to6-membered heterocyclic ring; wherein any C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, phenyl, 5- or 6-membered or heteroaryl, C₃₋₆cycloalkyl,—O—C₃₋₆cycloalkyl, heterocyclyl or —O-heterocyclyl (carbon-linked) isoptionally further substituted by one or more substituents selected fromC₁₋₂alkyl, cyano, C₁₋₂haloalkyl, hydroxy, C₁₋₂ alkoxy, halo,C₁₋₂haloalkoxy, NR_(1ea)R_(1fa) or —S(O)₀₋₂R_(1ea)R_(1fa), whereinR_(1ea) and Rita are H or C₁₋₂alkyl. (v) R₂₁, R₂₄ and R₃₀, areindependently selected from hydrogen or methyl; (vi) R₂₈ and R₂₉ areselected from hydrogen or halo, methoxy and methyl.
 16. A compoundaccording to any one of the preceding claims, or a pharmaceuticallyacceptable salt thereof, wherein R₁₇ is selected from hydrogen, halo,cyano, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, C₂₋₄alkenyl, C₂₋₄ alkynyl, C₃₋₆cycloalkyl, —O—C₃₋₄cycloalkyl, heterocyclyl,—(OCH₂CH₂)_(m)—OCH₃ wherein m is 1, 2 or 3, NR_(q)R_(r), wherein R_(q)and R_(r) are each independently hydrogen or C₁₋₂ alkyl; wherein anyC₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl or ring system is optionallysubstituted by one or more substituents selected from C₁₋₂alkyl,C₁₋₂haloalkyl, cyano, hydroxy, C₁₋₂alkoxy, halo and C₁₋₂haloalkoxy. 17.A compound according to any one of the preceding claims, or apharmaceutically acceptable salt thereof, wherein Z is selected from:

A₁, A₂, A₅, A₆, A₇, A₈, A₉, A₁₁, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁,R_(Y5N), R_(Z1), R_(Z2), R_(Z10), R_(Z12), R_(Z13), R_(Z14), R_(Z15),R_(Z16), R_(Z2a), R_(Z3a), R_(Z1a), R_(Zi1b) and R_(Zi2e) are as definedin any one of the preceding claims.
 18. A compound according to claim 1,or a pharmaceutically acceptable salt thereof, wherein: X is

Y is selected from:

and Z is selected from:

wherein: (i) R_(1a), R_(1b), R_(2a), R_(2b) and R_(2d) are as defined inany one of the preceding claims; (ii) R_(3a1), R_(3a2), R_(3b1),R_(3b2), R_(3i1), R_(3i2), R_(3j1), R_(3j2) and n are as defined in anyone of the preceding claims; and (iii) A₁, A₂, A₅, A₆, A₇, R₄, R₅, R₆,R₈, R₉, R₁₀, R₁₁, R_(Z1), R_(Z2), R_(Z10), R_(Z12), R_(Z13), R_(Z14),R_(Z15), R_(Z16), R_(Z2a), R_(Z3a), R_(Zi2e), R_(Zi1b) and R_(Z2) are asdefined in any one of the preceding claims.
 19. A compound according toclaim 1, or a pharmaceutically acceptable salt thereof, wherein: X is

Y is

and Z is

(i) wherein R_(1a), R_(1b), R_(2a), R_(2b) and R_(2d) are as defined inany one of the preceding claims; (ii) n, R_(3a1) and R_(3a2) are asdefined in any one of the preceding claims; and (iii) A₁, A₂, R₄, R₅ andR₆ are as defined in any one of the preceding claims.
 20. A compound, ora pharmaceutically acceptable salt thereof, selected from any one of thefollowing:N-({2-[(4,4-dimethylpiperidin-1-yl)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamideN-[(2-{[(cyclobutylmethyl)amino]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamideN-[[2-[[(3,3-difluorocyclobutyl)methylamino]methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamideN-[[2-[[(1-hydroxycyclobutyl)methylamino]methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamideN-[[2-[[(1-fluorocyclobutyl)methylamino]methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamideN-[[2-[[(1-methylcyclopropyl)methylamino]methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide.N-[[2-(2-azabicyclo[2.1.1]hexan-2-ylmethyl)-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamideN-[[2-(3-azabicyclo[3.1.1]heptanean-3-ylmethyl)-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamideN-[[2-[[2-(hydroxymethyl)pyrrolidin-1-yl]methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamideN-[[2-(morpholinomethyl)-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamideN-[[2-[(1-adamantylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide4-oxo-N-[[2-(1-piperidylmethyl)-1H-indol-6-yl]methyl]pyrido[1,2-a]pyrimidine-2-carboxamideN-[[2-[(4-fluoro-1-piperidyl)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide4-oxo-N-[[2-[[[rac-(1S,2S,4S)-7-oxabicyclo[2.2.1]heptane-5-en-2-yl]methylamino]methyl]-1H-indol-6-yl]methyl]pyrido[1,2-a]pyrimidine-2-carboxamideN-[[2-[[(1-hydroxycyclopentyl)methylamino]methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide4-oxo-N-[[2-[[[rac-(1S,2R,4S)-7-oxabicyclo[2.2.1]heptane-5-en-2-yl]methylamino]methyl]-1H-indol-6-yl]methyl]pyrido[1,2-a]pyrimidine-2-carboxamideN-[[2-[(1-bicyclo[1.1.1]pentanylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamideN-[[2-[(cyclobutylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamideN-({2-[({bicyclo[2.2.1]heptanean-2-yl}amino)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamideN-[[2-[(cyclopropylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamideN-[[2-(2-azabicyclo[2.2.2]octan-2-ylmethyl)-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamideN-[[2-[[(2,2-difluorocyclopropyl)methylamino]methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamideN-[(2-{[({3-fluorobicyclo[1.1.1]pentan-1-yl}methyl)amino]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamideN-[[2-[(cyclohexylmethylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamideN-[[2-[[(1-hydroxycyclohexyl)methylamino]methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamideN-[[2-[(cyclopentylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamideN-[[2-[(cyclopentylmethylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamideN-[[2-[[(1-methoxycyclobutyl)methylamino]methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamideN-[[2-[(isobutylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamideN-[[2-[(cyclohexylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamideN-[[2-[(cyclopropylmethylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide4-oxo-N-[[2-[(prop-2-ynylamino)methyl]-1H-indol-6-yl]methyl]pyrido[1,2-a]pyrimidine-2-carboxamideN-[[2-[(oxetan-2-ylmethylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamideN-[[2-[(2,2-dimethylpropylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamideN-[[2-[(1-bicyclo[1.1.1]pentanylmethylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamideN-{[2-({[(1S,2S)-2-hydroxycyclopentyl]amino}methyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamideN-{[2-({[(1R,2R)-2-hydroxycyclopentyl]amino}methyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamideN-{[2-({[(1S,2R)-2-hydroxycyclopentyl]amino}methyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamideN-{[2-({[(1R,2S)-2-hydroxycyclopentyl]amino}methyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamideN-[[2-[(cyclopropylmethylamino)methyl]-5-fluoro-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamideN-[[2-[(cyclobutylmethylamino)methyl]-5-fluoro-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide4-oxo-N-[[2-[(2,2,2-trifluoroethylamino)methyl]-1H-indol-6-yl]methyl]pyrido[1,2-a]pyrimidine-2-carboxamideN-[(2-{[N-(cyclobutylmethyl)acetamido]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide4-oxo-N-{[2-(piperidin-2-yl)-1H-indol-6-yl]methyl}-4H-pyrido[1,2-a]pyrimidine-2-carboxamideN-[(2-{[(cyclobutylmethyl)amino]methyl}-3-fluoro-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamideN-[(2-{[(cyclobutylmethyl)amino]methyl}-1-methyl-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamideN-[[2-[(Cyclobutylmethylamino)-dideuterio-methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamideN-[[2-[(cyclobutylmethylamino)methyl]-1H-indol-6-yl]methyl]-1H-indazole-4-carboxamideN-[[2-[(cyclobutylmethylamino)methyl]-1H-pyrrolo[3,2-b]pyridin-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamideN-(1H-indol-6-ylmethyl)-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamideN-(1H-indol-2-ylmethyl)-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamideN-(indolizin-2-ylmethyl)-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamideN-[(6-{[4-(1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl]methyl}-1H-indol-2-yl)methyl]cyclopropanamine(1R,2S)-2-[[6-[[4-(1H-indazol-4-yl)triazol-1-yl]methyl]-1H-indol-2-yl]methylamino]cyclopentanolN-[[6-[[4-(1H-indazol-4-yl)triazol-1-yl]methyl]-1H-indol-2-yl]methyl]cyclopentanamineN-(cyclopropylmethyl)-1-[6-[[4-(1H-indazol-4-yl)triazol-1-yl]methyl]-1H-indol-2-yl]methanamine1-[[[6-[[4-(1H-indazol-4-yl)triazol-1-yl]methyl]-1H-indol-2-yl]methylamino]methyl]cyclobutanolN-(cyclobutylmethyl)-1-[6-[[4-(1H-indazol-4-yl)triazol-1-yl]methyl]-1H-indol-2-yl]methanamineN-(cyclobutylmethyl)-1-[6-[[4-(1H-indazol-4-yl)triazol-1-yl]methyl]-1H-pyrrolo[3,2-b]pyridin-2-yl]methanamineN-(cyclobutylmethyl)-1-[6-[[4-(1H-indazol-4-yl)triazol-1-yl]methyl]-1H-pyrrolo[3,2-c]pyridin-2-yl]methanamineN-(cyclobutylmethyl)-1-[6-[[4-(1H-indazol-4-yl)triazol-1-yl]methyl]-1H-pyrrolo[3,2-c]pyridin-2-yl]methanamine2-[1-[[2-[(cyclobutylmethylamino)methyl]-1H-indol-6-yl]methyl]triazol-4-yl]pyrido[1,2-a]pyrimidin-4-oneN-(cyclobutylmethyl)-1-[6-[[4-(6-methoxyimidazo[1,5-a]pyridin-8-yl)triazol-1-yl]methyl]-1H-indol-2-yl]methanamineN-(cyclobutylmethyl)-1-[6-[[4-(1H-indazol-4-yl)imidazol-1-yl]methyl]-1H-indol-2-yl]methanamineN-(cyclobutylmethyl)-1-[6-[[3-(1H-indazol-4-yl)-1,2,4-oxadiazol-5-yl]methyl]-1H-indol-2-yl]methanamineN-[[2-(2-azaspiro[3.3]heptanean-2-ylmethyl)-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamideN-[[2-[(benzylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamideN-[[2-(3-azabicyclo[3.1.0]hexan-3-ylmethyl)-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamideN-[[2-[[cyclobutylmethyl(methyl)amino]methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamideN-[[2-[(cyclobutylmethylamino)methyl]-1H-pyrrolo[2,3-b]pyridin-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamideN-[(2-{[(cyclobutylmethyl)amino]methyl}-1H-1,3-benzodiazol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamideN-[(2-{[(but-2-yn-1-yl)amino]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamideN-[(2-{[(3-cyclopropylprop-2-yn-1-yl)amino]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamideN-({2-[({bicyclo[3.1.0]hexan-6-yl}amino)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamideN-[(2-{[({bicyclo[2.1.1]hexan-1-yl}methyl)amino]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamideN-[(2-{[({3-methylbicyclo[1.1.1]pentan-1-yl}methyl)amino]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamideN-({2-[(3-methylazetidin-1-yl)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamideN-({2-[(3-fluoroazetidin-1-yl)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamideN-({2-[(azetidin-1-yl)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamideN-{[2-({2-azaspiro[3.4]octan-2-yl}methyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamideN-({2-[(3-hydroxyazetidin-1-yl)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamideN-({2-[(3,3-dimethylazetidin-1-yl)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide4-oxo-N-[(2-{[3-(2,2,2-trifluoroethoxy)azetidin-1-yl]methyl}-1H-indol-6-yl)methyl]-4H-pyrido[1,2-a]pyrimidine-2-carboxamideN-[(2-{[3-(difluoromethyl)azetidin-1-yl]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamideN-({2-[(3-methoxyazetidin-1-yl)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamideN-[(2-{[3-(tert-butoxy)azetidin-1-yl]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide4-oxo-N-[(2-{[3-(trifluoromethyl)azetidin-1-yl]methyl}-1H-indol-6-yl)methyl]-4H-pyrido[1,2-a]pyrimidine-2-carboxamideN-({2-[(3-ethoxyazetidin-1-yl)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamideN-{[2-({2-azaspiro[3.5]nonan-2-yl}methyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamideN-({2-[(2-methylazetidin-1-yl)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamideN-({2-[(3,3-dimethylpyrrolidin-1-yl)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamideN-{[2-({6-fluoro-2-azaspiro[3.3]heptanean-2-yl}methyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamideN-{[2-({6,6-difluoro-2-azaspiro[3.3]heptanean-2-yl}methyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamideN-({2-[(3-cyclobutylazetidin-1-yl)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamideN-({2-[(3-cyclopropylazetidin-1-yl)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamideN-({2-[(3-tert-butylazetidin-1-yl)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamideN-[(2-{[(1-tert-butylcyclopropyl)amino]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamideN-{[2-({[(3-methylcyclobutyl)methyl]amino}methyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide4-oxo-N-[(2-{[(2,3,3-trimethylbutan-2-yl)amino]methyl}-1H-indol-6-yl)methyl]-4H-pyrido[1,2-a]pyrimidine-2-carboxamideN-[(2-{[({imidazo[1,2-a]pyridin-2-yl}methyl)amino]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamideN-({2-[(3,3-diethylazetidin-1-yl)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide4-oxo-N-[(2-{[(pent-3-yn-1-yl)amino]methyl}-1H-indol-6-yl)methyl]-4H-pyrido[1,2-a]pyrimidine-2-carboxamideN-{[2-({6-azaspiro[3.4]octan-6-yl}methyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamideN-({2-[(2,2-dimethylpyrrolidin-1-yl)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamideN-{[2-({octahydrocyclopenta[c]pyrrol-2-yl}methyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamideN-{[2-({5-azaspiro[2.4]heptanean-5-yl}methyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamideN-[(2-{[({3-methoxybicyclo[1.1.1]pentan-1-yl}methyl)amino]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide4-oxo-N-[(2-{[({spiro[2.2]pentan-1-yl}methyl)amino]methyl}-1H-indol-6-yl)methyl]-4H-pyrido[1,2-a]pyrimidine-2-carboxamide4-oxo-N-({2-[({spiro[2.3]hexan-1-yl}amino)methyl]-1H-indol-6-yl}methyl)-4H-pyrido[1,2-a]pyrimidine-2-carboxamideN-[(2-{[({3-cyanobicyclo[1.1.1]pentan-1-yl}methyl)amino]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamideN-{[2-({1-oxa-6-azaspiro[3.4]octan-6-yl}methyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamideN-{[2-({2-azaspiro[4.4]nonan-2-yl}methyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamideN-[(2-{[(1-methylcyclopentyl)amino]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamideN-{[2-(hydroxymethyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamideN-[(2-{[(1-cyclobutylcyclopropyl)amino]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamideN-{[2-({[(1-methylcyclobutyl)methyl]amino}methyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide4-oxo-N-[(2-{[({spiro[2.3]hexan-5-yl}methyl)amino]methyl}-1H-indol-6-yl)methyl]-4H-pyrido[1,2-a]pyrimidine-2-carboxamideN-({2-[({[3-(fluoromethyl)bicyclo[1.1.1]pentan-1-yl]methyl}amino)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamideN-[(2-{[(1-{3-fluorobicyclo[1.1.1]pentan-1-yl}ethyl)amino]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamideN-({2-[(tert-butylamino)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide4-(1-{[2-({2-azaspiro[3.3]heptanean-2-yl}methyl)-1H-indol-6-yl]methyl}-1H-1,2,3-triazol-4-yl)-1H-indazoleN-{[2-(2-{2-azaspiro[3.3]heptanean-2-yl}ethyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide({3-fluorobicyclo[1.1.1]pentan-1-yl}methyl)({6-[(4-{imidazo[1,5-a]pyridin-8-yl}-1H-1,2,3-triazol-1-yl)methyl]-1H-indol-2-yl}methyl)amineN-[(2-{[({3-fluorobicyclo[1.1.1]pentan-1-yl}methyl)amino]methyl}-1H-indol-6-yl)methyl]-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-7-carboxamideN-[(2-{[({bicyclo[1.1.1]pentan-1-yl}methyl)amino]methyl}-1H-pyrrolo[3,2-b]pyridin-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamideN-[(2-{[({3-fluorobicyclo[1.1.1]pentan-1-yl}methyl)amino]methyl}-1H-pyrrolo[3,2-b]pyridin-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamideN-[(2-{[(cyclobutylmethyl)amino]methyl}-1H-pyrrolo[3,2-b]pyridin-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamideN-[(2-{[({3-methylbicyclo[1.1.1]pentan-1-yl}methyl)amino]methyl}-1H-pyrrolo[3,2-c]pyridin-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamideN-[(2-{[(cyclobutylmethyl)amino]methyl}-1H-pyrrolo[3,2-c]pyridin-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamideN-[(2-{[({bicyclo[1.1.1]pentan-1-yl}methyl)amino]methyl}-1H-pyrrolo[3,2-c]pyridin-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamideN-[(2-{[({3-fluorobicyclo[1.1.1]pentan-1-yl}methyl)amino]methyl}-1H-pyrrolo[3,2-c]501yridine-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamideN-[(2-{[(cyclobutylmethyl)amino]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H,6H,7H,8H,9H-pyrido[1,2-a]pyrimidine-2-carboxamide(cyclobutylmethyl)({6-[(4-{1H-pyrrolo[2,3-b]pyridin-5-yl}-1H-imidazol-1-yl)methyl]-1H-indol-2-yl}methyl)amine(cyclobutylmethyl)({6-[(4-{imidazo[1,5-a]pyridin-8-yl}-1H-1,2,3-triazol-1-yl)methyl]-1H-indol-2-yl}methyl)amineN-[(2-{[(2,2-dimethylpropyl)amino]methyl}-1H-indol-6-yl)methyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxamideN-[(2-{[(cyclobutylmethyl)amino]methyl}-1H-indol-6-yl)methyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxamide(cyclobutylmethyl)({6-[(4-{1H-pyrrolo[2,3-b]pyridin-5-yl}-1H-1,2,3-triazol-1-yl)methyl]-1H-indol-2-yl}methyl)amineN-[[2-(2-azabicyclo[2.2.1]heptanean-2-ylmethyl)-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamideN-[(3-fluoro-1-bicyclo[1.1.1]pentanyl)methyl]-1-[6-[(4-imidazo[1,5-a]pyridin-8-yltriazol-1-yl)methyl]-1H-pyrrolo[3,2-c]pyridin-2-yl]methanamine(cyclobutylmethyl)[(6-{[1-(1H-indazol-4-yl)-1H-1,2,3-triazol-4-yl]methyl}-1H-indol-2-yl)methyl]amine[(3,3-difluorocyclobutyl)methyl][(6-{[1-(1H-indazol-4-yl)-1H-1,2,3-triazol-4-yl]methyl}-1H-indol-2-yl)methyl]amine(cyclobutylmethyl)[(6-{[1-(isoquinolin-4-yl)-1H-1,2,3-triazol-4-yl]methyl}-1H-indol-2-yl)methyl]amine(cyclobutylmethyl)({6-[(1-{imidazo[1,5-a]pyridin-8-yl}-1H-1,2,3-triazol-4-yl)methyl]-1H-indol-2-yl}methyl)amine.3-[1-({2-[({(Bicyclo[1.1.1]pent-1-yl)methyl}amino)methyl]-1H-indol-6-yl}methyl)-1H-1,2,3-triazol-4-yl]-5-methoxy-2-pyridinecarbonitrile;3-[1-({2-[({(3-Fluorobicyclo[1.1.1]pent-1-yl)methyl}amino)methyl]-1H-indol-6-yl}methyl)-1H-1,2,3-triazol-4-yl]-5-methoxy-2-pyridinecarbonitrile;5-Methoxy-3-[1-({2-[({(3-methylbicyclo[1.1.1]pent-1-yl)methyl}amino)methyl]-1H-indol-6-yl}methyl)-1H-1,2,3-triazol-4-yl]-2-pyridinecarbonitrile;3-{1-[(2-{[(Cyclobutylmethyl)amino]methyl}-1H-indol-6-yl)methyl]-1H-1,2,3-triazol-4-yl}-5-methoxy-2-pyridinecarbonitrile;3-{1-[(2-{(6-Aza-6-spiro[3.4]octyl)methyl}-1H-indol-6-yl)methyl]-1H-1,2,3-triazol-4-yl}-5-methoxy-2-pyridinecarbonitrile;3-[1-({2-[(4,4-Dimethyl-1-piperidyl)methyl]-1H-indol-6-yl}methyl)-1H-1,2,3-triazol-4-yl]-5-methoxy-2-pyridinecarbonitrile;N-((2-((6-azaspiro[3.4]octan-6-yl)methyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide;3-(1-((2-(((cyclobutylmethyl)amino)methyl)-1H-indol-6-yl)methyl)-1H-1,2,3-triazol-4-yl)-5-fluoropicolinonitrile;1-cyclobutyl-N-((6-((4-(5-methoxypyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)-1H-indol-2-yl)methyl)methanamine;5-chloro-3-(1-((2-(((cyclobutylmethyl)amino)methyl)-1H-indol-6-yl)methyl)-1H-1,2,3-triazol-4-yl)picolinonitrile;and2-((6-azaspiro[3.4]octan-6-yl)methyl)-6-((4-(imidazo[1,5-a]pyridin-8-yl)-1H-1,2,3-triazol-1-yl)methyl)-1H-pyrrolo[3,2-c]pyridine.21. A pharmaceutical composition comprising a compound according to anyone of claims 1 to 20, or a pharmaceutically acceptable salt thereof,and one or more pharmaceutically acceptable excipients.
 22. A compoundaccording to any one of claims 1 to 20, or a pharmaceutically acceptablesalt thereof, or a pharmaceutical composition according to claim 21, foruse in therapy.
 23. A compound according to any one of claims 1 to 20,or a pharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition according to claim 21, for use in the treatment of aproliferative condition.
 24. A compound according to any one of claims 1to 20, or a pharmaceutically acceptable salt thereof, or apharmaceutical composition according to claim 21, for use in thetreatment of cancer.
 25. A compound according to any one of claims 1 to20, or a pharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition according to claim 21, for use in the treatment ofleukaemia.
 26. compound according to any one of claims 1 to 20, or apharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition according to claim 21, for use in the treatment of anautoimmune disease, a neurological disease, an inflammatory disease, aninfectious disease or a disease related to the re-activation of thesilenced X-chromosome.